The Dark Side of the Decade

This post is the sequel to my short review of the last decade of positivity in MND/ALS research. Like that article, this draws on my own experience since diagnosis.

However, this time, welcome, like it or not, to……. The Dark side of the Decade.

Yes, I’m deliberately focusing on the negatives: the cracks, flaws and frustrations. Some things from the past ten years don’t just feel wrong, they are, in my opinion, slowing progress and we really should learn from them. I, perhaps naively, remain an eternal optimist, convinced we can make progress with all of these ‘difficulties’, and I do feel the need to be frank. Think of this as perhaps an accident investigation, and we have to examine the wreckage so that the lessons might appear. I don’t use the word wreckage lightly either!

I give air to both items of concern that have emerged since the day of my dreaded diagnosis and things, that, as my father used to say, have probably been around since the ‘year dot’. 

Some readers might find my presentation of this a bit dramatic. Yes, that is my very intention. I really want you to read and let it stick in your mind. This is very real, and when first diagnosed, patients and families might not appreciate this Dark Side of research that is sadly there.

I am going to use some famous songs (you might recognise all of them, depending on your age!) as headings for the rest of this post and these titles might just say more than I do in the text! The first one is what we old timers called a double A side!

Silence has been a constant presence in MND/ALS research. Trials that vanish, drug candidates which stall or fade, and even scientists who sometimes stop communicating altogether.

There is also white noise, not silence at all, but the drip‑drip of public communications (particularly picked up by patients and families), often about nothing consequential, yet constant enough to create the impression of progress.

I fully recognise that investors expect updates. They have every right to know what’s happening with their money. But many of these updates mislead our community, either by overstating what the information actually means or by implying progress where none exists.

A trivial example is the biotech habit of reporting minutiae. Paraphrased:

“We had a meeting with regulators. Nothing substantive happened, but we’re telling you anyway.”

These communications don’t move science forward. They simply fill the space so no one notices that nothing has changed.

But often the white noise is far more concerning. From the continued re-analysis of existing data in posters at conferences and in press releases, the high level process chatter as opposed to science, to partnership interest/discussions which never materialise.

To be clear, many drug candidates are progressing responsibly, and sponsors report trials openly. That’s encouraging. But silence and white noise surrounds others, and it matters.

At the very least we should all be aware of these challenges.

Here are but a few examples of drug treatment candidates, ones that have been around since my diagnosis or earlier! They are all still bubbling….

• CuATSM (CMD) – since early 2000s
• Nurown (Brainstorm) – since 2013
• Low‑dose IL2 (ILTOO – Mirocals consortium) – since 2015
• CNM‑AU8 (Clene) – since 2010
• Masitinib (AB Science) – since 2010
• Tegoprubart – formerly AT-1501 – formerly ALSTDI-846 (ALSTDI/Eledon Pharma) – since 2010
• PrimeC (Neurosense) – since 2017
• ILB (Tikomed) – since 2007

What’s going on in each of these!? Why the delays? Just look at the time they have been around our community and the research/industry space! Aside perhaps some of the static noise I mentioned above, ask yourself some of the following questions.

• Have the sponsors run out of money or failing to raise further amounts?
• Have results been delayed or never published in journals?
• Do some companies refuse to admit failure, keeping projects alive in a sort of “Neverland”?
• Have the trials ended with results that just don’t convince scientific financial investors but sponsor is holding on to exclusivity benefits?
• What role might orphan drug benefits play in some of this silence and limbo? For example, the benefits can provide exclusivity enabling biotech to shelve candidates quietly whilst funding is sought, however, long it might take.
• Are there Intellectual Property disputes occurring that are stalling progress?
• Has any delay been caused by prioritising the same drug in other diseases first?
• Has the delay been extended further once those rights were sold or licensed elsewhere?
• Has the delay been the result of progress happening everywhere except in MND itself?
• Has the delay been worsened by shifting resources and timelines away from the MND indication?

The resultant effect is what we often see today, and that is a façade of activity when, in reality, many drugs are as lifeless as the proverbial Monty Python parrot.

Let’s spin up the next Dark Side song!

Patient advocacy can be very powerful. It unites communities, raises awareness, and drives funding. But it can also cause harm, real harm.

Take, for example, the ACT for ALS bill in the USA. Driven by powerful advocacy, the bill aimed to give more patients access to experimental drugs. That sounds very admirable in principle, yes? In practice, to date the bill has handed out $125m, over four years in grants to pay pharma, hospitals and others for unproven treatments and as yet no drug accessed has made it anywhere near approval.

One drug alone, CNM‑AU8, received $45m despite lacking any pivotal trial evidence, which it still lacks today. Further the $125m did not provide access to thousands of patients, as you might have expected, but a mere 750, averaging a cost of $170k each! For unproven drugs!

Such funding risks incentivising companies to chase early stage payouts rather than genuine breakthroughs. In my view, this advocacy initiative has slowed progress rather than accelerated it.

Where is this going? Nowhere?

Meanwhile, here in the UK the entire government budget/grants available for MND/ALS research for the whole nation is just £10m ($13m) a year!! Feels kinda of wrong, yes?

Next on the Dark Side stacker is…

Underfunding research remains a major barrier, especially here in the UK. Even after the successful £50m United2EndMND campaign in 2021, researchers typically receive only £10m annually (in total) from the UK government, ongoing, for advancing research.

The fundamental issue with UK government funding is the absence of sustained ring fenced cash for MND/ALS. This lack, encourages unfettered competition over balanced and strong collaboration. The UK MND Research Institute is a step toward adjusting this balance, but more is needed. Without continued, secure, substantial, government investment into strategic research, progress will always be constrained.

Lets turn up the volume for the next tune!

Sensationalist press releases are a terrible blight.

We are told, by researchers, that they are for raising funds and meant for investors. Really?! Yes, they are often published by industry media. But it is foolish to believe that patients don’t read them. Social media clearly amplifies them, and patients pay the price in both false hope and division through misguided advocacy that might follow.

Such announcements trumpet “breakthroughs” or cherry-picked early trial statistics, often crafted by pharma or biotech. To be clear, they don’t invent data, but they present early exploratory numbers almost as gospel proof. That’s nothing other than misleading.

Researchers rarely challenge them, and sometimes even lend their names to the statements. The misuse of statistics is central here, a recurring theme in my writing. For patients, the effect is indistinguishable from lying, in my opinion.

Clinicians and lead researchers bear a responsibility here and there should be standards that they adhere to.

I don’t hold much hope in them changing in the short term but we all need to be aware of their existence and what they mean or more importantly what they don’t mean.

Let’s keep up the pace, straight on to another disc. This next one is a question really? Can we?

As aforementioned a lack of collaboration caused by funding structures is real and slowing research. But it is also a problem because human egos often get in the way. Academia is not immune to pride, and it can truly stifle progress. Enough said!

I’ve taken a bit of a liberty with this next one, as it’s not really about law, but you will get the gist!

Regulation is another stinking great issue. Approval processes, especially here in the UK, are slow and ill‑prepared for the pace of this disease.

United2EndMND highlighted this in their post “Now that would be a nice problem to have, or would it?”

There is a very real risk that even if true breakthroughs arrive, bureaucracy may hold them back. In fact, it has already happened with tofersen in the UK over the last 2 years. The effect is people are suffering real clinical harm and even dying because there is an effective treatment available but they cannot access.

I now want to end this rather negative, but cautionary, post with an optimistic thought. 

AI is everywhere, advancing so quickly that my words may already be dated. Yes, I might have even passed my best before date, guys!

AI won’t deliver miracles, but the current capabilities are already truly extraordinary.

The ‘intelligence’, for example, within the field I spent my career in, software development, is breathtaking for anyone who has toiled over the technology, often over night, for a living.

Beyond the obvious use for drug discovery in MND/ALS, I see huge potential in how AI could reshape communication, ie many of the very issues raised in this post.

• Reviewing and analysing scientific papers
• Interpreting trial results
• Spotting statistical misuse
• Helping patients understand viability

Could AI replace journal reviewers? Assist researchers? Empower patients? In my view, yes. The challenge is how leaders choose to respond.

I’ll decide on my next “Devil Detail” post soon, and the odds are very high it will be about statistics (apologies for the awful pun).

See you all soon, folks!