A therapy and cure!!

This is my May 2017 Research Opinion Update, and contains news! Since my January post, the FDA in the USA, on Friday 5th May, has approved the first new drug in over 22 years for MND/ALS, Edaravone!

It is important to say, right here and now, that this is NOT a game changing or disease halting drug, BUT a very real step towards the ultimate aim, i.e. a disease stopping therapy or an actual cure. Suffice to say, the FDA does not ever lightly approve a drug. This is serious stuff.

I had prepared this post before the Edaravone news was released.  So, I will now return to the main theme and comment on the announcement as appropriate.

So let’s get back to that road to a therapy….

Research and clinical drugs trials are the main battleground against disease. Many diseases have been overcome through science and in particular, the clinical trial process.

Yet, you may hear statements such as

Why are they so slow in developing a therapy and why are there so few trials in the UK?”

“Why does it take so long to get a promising drug available?

Why are the authorities, including the FDA in the USA, so bureaucratic?

This post will answer these questions and more!

In fact I will answer the last question now. Whenever I hear this, I search for the detail of the complainant’s issue. Typically it always relates to scientific process as opposed to actual bureaucracy, ie the two first questions. It is an argument often used to attack authorities but without any real validity. Obviously there may be some real bureaucracy; complicated form filling or process here and there, for example. I do not see bureaucracy as a real issue.

In my January opinion update I described 2 drugs that had completed extensive Phase 3 trials, the final major hurdle that has to be overcome before any drug approval can be considered.

1. Edaravone

As already stated, this drug has now been approved in the USA. It is not yet approved in Europe or the UK.

Here is the very considered, timely and most appropriate initial response from the UK MND Association.

Here are my thoughts…

The drug has very specifically shown some effectiveness in very early disease patients, at slowing the progression, but neither stopping or reversing the disease. So there will be a lot of quite correct discussions regarding cost/benefit. The press headline states a 33% reduction in rate of decline. Wow that sounds good, doesn’t it? This reduction was over a 6 month study, and the patients still all declined by an average of 5.01 ALSFRS-R points in that time. We only have 48 points to lose! However, it is a slowing and the implications for all patients cannot be accurately predicted. For example, it is quite plausible, but there is no evidence, that some may see more significant slowing. This is why even a small proven significant change in a trial is worth further investigation.

One aspect of the currently approved Edaravone drug formulation is that it has to be intravenously (IV) administered. A pill form is being researched and trialled by a company called Treeway. However, it is not currently clear at what stage this work is at. I am trying to find out. I suspect there may be some escalation/increased interest now with the FDA approval in the USA.

In my view, based on the current reported efficacy, the pill form will be required if this drug is to be widely used, if and when approved in the UK.

So all in all, good news!

2. Masitinib

Like Edaravone, a Phase 3 trial has, according to the pharmaceutical company (AB Science), shown some efficacy and they claim “stronger” effects than Edaravone. No precise detail has yet been made public and they are liaising with regulators in Europe. From my reading it appears that a decision might be due in the next 6/12 months.

Masitinib is a pill. Consequently, in my view, this drug, if approved, might find more of an accelerated path in Europe. A repeat Phase 3 confirmatory trial is planned. This week, AB Science (18th May) will be presenting the final detailed trial results at the ENCALS Conference in Slovenia. I wait in anticipation.

So after 20 years of disappointing and failed trials, there is now real progress happening.

So let’s now look at the question as to why there appear to be not many, if any trials, in the UK. Keeping it short, there is actually a vast amount of work going on that is pre-clinical. “What is this Lee?” To understand why this is important, I need to describe a little about the trial process.

Here is onein400’s guide to what these stages really mean, what happens, what has happened and aspects you should take note of.

In my view this process is unchallengeable as the method to solve disease. You may hear of adaptive trials in the press and some health media. These are in the large part fine tuning and some adaptive trials are slightly controversial and can lead to bias and/or very weak statistics.

The size of the y axis on my chart represents the amount of work/drugs/techniques currently in progress. As you can see pre-clinical the largest. Pre-clinical work is the study of the disease process and non human clinical trials.

What is mostly spoken about in public are the stages of human testing, i.e. Phases 1,2 and 3. In reality these are the tip of the iceberg.

A drug or technique will only move to Phase 1 when there is evidence of a method of action and a consensus that it is worth taking further with the funds to carry out human trials.

Phase 1 is all about safety. This is a relatively small trial, potentially on all healthy cases, and/or mixed controls/cases. It is designed to simply ensure the human body does not blow up! No more, no less.

Phase 2 will proceed if a drug doesn’t destroy the human body, and this will start to look for signs of efficacy, i.e. disease modifying effects.

Now before we jump to Phase 3, some important observations.

Observation 1

It is possible, depending on the disease and drug, that Phase 1 or Phase 2 might show radical disease efficacy!! For example, if a significant number of patients all suddenly started to improve dramatically, this would possibly, and has in the past, meant that a drug might just be approved before Phase 3. For MND, owing to the disease measuring issues, and variability of disease presentation, this currently will almost certainly not happen. Why?

To solve a disease like MND we need to;

1. Truly understand the disease process and target drugs at specific steps.
2. Be able to measure the disease progression precisely.

If we have neither of the above, no amount of adapting trials, changing criteria will ever help. Where are we with MND? We have hints of targets, but we have nothing more than the ALSFRS-disease measurements.

Observation 2

The following observation is a cold hard fact. I won’t go into the mathematical calculations, but for MND, trials may need up to about 350 patients over a time period of typically 18 to 24 months to reach statistical significance. It simply cannot be quicker. So in answer to one of my first questions, scientists are working as fast as the current proof elements dictate.

So if a drug shows some efficacy, and it is not a wonder drug, it is then time to move on to Phase 3.

Observation 3

It could be said that if only small signs of efficacy have been shown and a comprehensive Phase 3 is required, it is actually almost certain that the drug is going to be a small effect drug at best or a specific sub group of patients may benefit more than others.

So one thing to bear in mind, if a drug is press released “as promising and undergoing Phase 3 trials“, it is almost certainly a small effect drug.

Jeesh Lee, this sounds all bad!

No, not in the least bit. Returning to the trial stages above. Although it may appear that there are not many trials, the vast amount of work is pre-clinical. The effort here is exploding and lots of new leads are being found monthly. My featured image on this post represents this with bubbles of ideas and drug leads appearing close to, with bubbles bursting as time moves forward, with only a few making it through the entire process. In reality the windscreen is now totally packed, and a lot of this work is happening here in the UK.

I will add one caveat to my comments regarding trial adaptation. During the trials of Edaravone, new “groups” of patients were targeted/analysed. In the early Phase 3 trials no effect was detected, but then by selecting new sub groups, specifically early diagnosed patients, an effect was revealed.

I will just mention one UK clinical human trial that is starting imminently and the project is called;


This is targeting the anti-inflammatory qualities of Interleukin 2(IL2).  IL2 is already used with various diseases to reduce the immune reaction to disease.

There is a basic premise behind how IL2 might help MND patients….

MND is a progressive disease. It gets worse and spreads throughout the body. It is how the disease spreads that is currently a real mystery. Is it a “toxin” that spreads? Does it arise spontaneously throughout the body? Or is it a combination of different processes in separate regions? There is some evidence that perhaps the immune system actually turns rogue and attacks the motor neurones and this process, “inflammation”, effectively helps spread the disease or some aspects of the disease. It is well-known that there is a whole spectrum of disease manifestation with some having a disease which runs at a pace which is quite literally breathtaking, whilst others show aspects of the disease and progress much slower.

This Mirocals trial is of significant size and timeframe and will be looking for disease slowing and also potential new biomarkers that could be used for faster future trials.

Lots of great pre-clinical work is driving the fight against MND!

There will now be a rise of moving from core research to increased treatment evaluation, so-called translational research.

Gene therapy remains, in my view, the most likely source of a big breakthrough in the next 10 years, and just in the time I started writing this post, 2 new genes have been found linked to MND/ALS!!!  I was going to write about them, but it’s too early. These are really exciting times.

Finally, what am I personally going to do regarding Edaravone?

Well, it’s not yet approved or available in the UK. It has to be IV delivered. It would cost a lot if I purchased myself (from internet sources). No UK medic could inject it (Hippocratic oath would be broken) and it has a very mild effect. As a person living with MND, I am going to wait and see.

Masitinib could be a different story, if approved in Europe. It will be a pill form straight off the bat.

I will write a further update in 3 month time. By then there would have been some news, good or bad.