A nice mysterious title for a research opinion post? Read on, my intrigued and loyal followers….
Following my last research update, I promised a short post on personalised medicine. This seems very apt as the subject is talked about quite a lot in the media and in my last discourse I discussed specific genetic associations with MND.
Personalised medicine promises major and diverse health advances ranging from utilising drugs more efficiently through to drug trials targeted at specific individuals. There is no doubt in time, personalisation will evolve in ways we can’t even dream of now. However, it will take many years.
Where is the medical world with right now, today in 2018, with such personalised treatments?
Cancer is the best example of a disease (or more precisely, a group of diseases) that has quite literally 100s of drugs and other interventions (chemotherapy, radiotherapy and surgery) available. Steadily, practitioners are utilising genetic sequencing to help identify what might be the best drug to treat a tumour for a patient. It’s truly in its infancy. However, you will be pleased to hear that the UK is leading the way in Europe with genome screening/typing services now becoming available.
So for the cancers, personalised medicine capability is really moving ahead well and we will see better application of existing treatments as the very first benefit.
Now, let’s take a look at our disease, MND. It’s pretty simple, there is one drug, 22 years old, so there is no choice!
And to make things worse, there is not even a precise disease measure! I have spoken about so-called bio-markers before, for which we have none just yet.
As a bit of a reminder, just what is a bio-marker? A simple example is measuring a viral infection such as HIV. It is possible to take a blood sample and quantify the precise amount of virus in the blood. A drug’s efficacy can then be measured confidently and accurately. Cancers have an advantage in that they can be biopsied or scanned. A reduction in tumour size/or changes in density, can be a real measure of the disease change.
With MND we have nothing yet.
You cannot biopsy a neurone until after death and currently scans are not detailed enough to show them and their associated damage (although work is progressing in this field).
What we do have is the ALS/FRS-R rating scale, which for those are unaware of, you can read all about here. It is a subjective measure of disease, purely clinical and observational, and prone to error. So the search for bio-markers is vital.
The most likely breakthroughs for MND treatment will arise from a gene therapy for an identified gene association or other small disease-slowing drugs. But as mentioned in my earlier post we don’t, as yet, know how any gene associated with MND actually causes the disease*! To take this further, let’s take a current example of a currently ongoing trial, for SOD1 gene therapy. The trials are, naturally, only using participants that have the specific gene mutation.
*Important Post Update 8/8/18 – A recent publication actually emphasises the possibility of non gene mutation carriers potentially being affected by the same gene!!
Imagine, for one moment, that these trials show significant disease halting or slowing properties.
What are the immediate implications?
What do we do?
Do we offer the treatment only to such gene association identified patients?
Logically, the answer to the last question is “yes”. However, can we be sure that the actual disease causing process influenced by the treatment is not the same in patients without the identified mutation? The answer is currently NO, we can’t. And a further key fact is that the trials are only working with those participating in the trials.
“Hold on Lee, that last point is bleeding obvious!”
Yes it is. But I would contend that with the disease diversity, lack of precise disease variant diagnosis, the lack of general genetic testing and the all of the above, it really shouts – “Just get a treatment that works out to everyone“.
Controversial, yes, but unless we start picking off the cases we will NEVER make progress with MND medicine.
In this hypothetical situation let’s now imagine a safe and moderately effective treatment is being considered for approval.
I like these little mind benders because considering possible outcomes can help distill approaches and prepare for the real life situations.
To give you a bit more background, I would just like to describe one of the issues that can arise, and actually has done, in the drug approval history for MND.
The only drug we have for MND, Riluzole, was only tested/trialled on patients who had ALS. ALS is the main form of MND of which about 80% to 90% of all cases have. However, identifying who has it is still hard as it is all pure “clinical” observation. Now quite rightly, only consistent patients, with a similar disease progression, and other criteria were trialled. To cut a long story short, the drug does have some effect, but when it was finally approved in the UK, it was only approved for ALS patients.
All other MND sufferers were “technically” not eligible.
It is well known that some doctors just prescribe it for all MND patients and some are more reluctant. The reality is that for a small effect safe drug it’s harmless to prescribe for all, and no one knows if it works or not.
You see the issue? Translating the trial results into a drug approval process “dragged” through a potentially false restriction on it’s use. It happened!
Now wind the clock forward to today. The same danger is going to occur with perhaps an effective gene therapy (or other treatment) and what should we do?
If we can be 100% certain that ONLY people with a particular mutation will benefit, we should test patients, select and prescribe.
If not, do we then carry out a new trial on wider groups? With the lack of bio-markers, this will take 2 years at least potentially. And what then are the selection criteria?
Remember, the typical lifetime of someone with MND is two years post diagnosis. Stephen Hawking was totally unique.
So we have the very real danger of wrongly denying patients treatment, that might their lives, and of course we would still have only 2 treatments! This is the fundamental issue.
You might say that we should be precise. However, currently even with cancer, a lot of today’s treatment is still actually “chuck what we have” at most cases (clinical judgement) and see what works rather than personalised medicine. But there is wide choice of 10s of drugs in some cases.
I can envisage there being potential uproar in the community considering MND’s prognosis. Adding to this, the heterogeneity of MND cases, further trials may be fruitless and/or not possible. So again, we may end up with treatment denial.
I will add one vital caveat now, and that is if we can measure some real bio-markers, this may be the game changer. It will then be possible to design individual trials of a treatment that can be rapidly assessed.
“So what do you propose, Lee?”
I propose that we, as patients and people affected by MND, should be aware of such issues, and raise with our relevant MND/ALS Disease associations at any possible appropriate opportunity to make our voices heard.
This will be become more apparent as time moves on. Let us guide and assist the people who are working with our best interests at heart to make the most appropriate decisions as and when the right time comes. This can range from trial design through to the actual drug approval processes. It is this latter area where real noise is important. Like anything in life, he/she who makes most noise gets most attention. When we have a potential light at the end of the tunnel, let us step on the accelerator early to get to that light!
Here in the UK our government is not hearing enough noise about MND. When a treatment comes along we want no barriers to its release. Only recently, following Stephen Hawking’s death, a question was asked in Parliament to which Jeremy Hunt (Health Secretary) responded. However, he had obviously been briefed incorrectly (not his fault) and he stated there were 24 trials in progress in the UK (there are actually only 2) and that in the last year £52m has been invested in MND Research!!
This figure is completely and utterly wrong. I can only assume it is the sum of all government investment in ALL Neurodegenerative diseases perhaps?
STOP PRESS – It was wrong! Take a look at the following update by a minister. It was clarified as just £4m! Even worse, this is for MND and associated neurological diseases!! It is awareness of such under funding that needs to be presented to the government to help highlight the greater need.
Back to that to that Weapon of Choice. What is needed?
1) More trials and drug candidates.
2) More noise at the highest levels indicating that MND is an “unmet” need.
3) To assist ambitious and innovative drug companies with whatever needs to be achieved with approval processes.
4) And to quickly reject false hopes.
So as I say, “What’s your weapon of choice?”
With cancer, 100s of drugs now and perhaps with MND in 3 years time we might, if lucky, have 2 drugs!
You would try both wouldn’t you?
Living with Motor Neurone Disease 