Memantine, Arbaclofen and now Bumetanide stumble
in clinical trials
(also the less well known Balovaptan, which Roche dropped in 2020).
Place your bets on Suramin, anyone?
Plus ça change, plus c'est la même chose
The more things change, the more they stay the same
The first week of the school year
brought two big surprises.
Monty, aged 18 with autism, came
top of the class in the math test. This
is a big win for bumetanide treatment, because 9 years ago Monty was effectively
innumerate. With a
huge effort by his Assistant, he had learnt how to read and write, but
even the most basic maths was beyond him.
That all changed in 2012 thanks to Professor Ben-Ari’s published research on
Bumetanide in autism.
The sad news that week was that the Phase 3 clinical trial of
Bumetanide for autism had been terminated early.
Paris, 7 September 2021 – Servier and
Neurochlore announce that no sign of effectiveness was observed in their two
phase 3 clinical studies assessing bumetanide versus placebo in the treatment
of Autism Spectrum Disorders (ASD) in children and adolescents. As a
consequence, Servier and Neurochlore have decided, by mutual agreement, on an
early termination of the two clinical studies in progress.
“The results of the phase 3 clinical studies
are a major disappointment,” declares Professor Yehezkel Ben-Ari, President of
Neurochlore. “Neurochlore’s teams will now analyze in detail the results of the
studies and potentially explore new approaches based on artificial
intelligence, which may enable us to identify sub-populations of people suffering
from Autism Spectrum Disorders, for whom bumetanide could be effective.
Bumetanide also did not pass the NEMO clinical trial, as a treatment for neonatal seizures back in 2015. This then made it a bit awkward to suggest that children with severe autism might lower their risk of developing epilepsy by taking bumetanide. Since this is a blog, I can speculate. I would imagine children with severe autism, who are bumetanide-responders, and who are treated from early childhood through to adulthood with this drug, will have a low incidence of developing seizures. Seizures develop in about 30% of those with severe autism (DSM3 autism) and are the leading cause of their early death.
If such an effective therapy shows no
benefit in a trial with 400 participants, something has gone seriously wrong.
I did ask one researcher friend, who
just replied bluntly that the trial must have been poorly constructed. I thought that was a bit brutal, even by my
standards.
Be honest and admit your limitations
Monty, aged 18, came top in maths
among 15 neurotypical 16 year olds. But
the 45 pupils in the year had been split into sub-groups. Two groups of 15 taking
extended maths and one group of 15 taking core maths. For some reason, because Monty has autism
they put him in the lower group.
Not to worry, after his coming top in
the math test, the school agreed that he can move to one of the upper groups
taking the wider math curriculum.
So Monty is no maths genius, he
came top among the weakest group of typical kids. That is the whole truth, which is different to
the partial truth.
In a similar way, autism
researchers need to accept that there may never be a unifying therapy for
autism, one that benefits everyone.
Concentrate on the responders to
your treatment and forget the rest. If
you over-sell your therapy, you will fail.
As I have said in this blog many
times, most people with an autism diagnosis are not bumetanide-responders. However, a significant minority of those with
severe autism are responders to bumetanide and they will experience a
transformative benefit.
Going from a basket case to a Maths Whizz even?
Apply common sense and don’t outsource everything
In previous clinical trials of
bumetanide, critics said it was all a placebo effect because the parents knew
when they were giving bumetanide rather than a placebo. The bumetanide pill causes the diuresis and
placebo does not.
Why can you not use a different
diuretic as the placebo? Answer that
one!
Many people using bumetanide give
up because of the diuresis. With
schoolkids, the parents will receive complaints from school about excessive
toilet breaks. There will be wetting of
trousers, car seats etc. There will be
anxiety caused by urgently needing a toilet, when none is nearby.
So you need a strategy in advance
of how to deal with the diuresis.
I was told that people in the one trial centre I know about, were told nothing about the diuresis and how to cope
with it. I was even told the clinician
basically told the parents that it was a stupid trial. Not a good way to ensure compliance with the
trial protocol.
So what happens? Some parents will
decide to stop giving the diuretic drug, at least on school days. Maybe they think that a “double-dose” at the
weekend will make up the difference.
Clinical trials are a business
these days and are outsourced to companies that do this and nothing else. Don't outsource the most critical part of your work, or at least supervise it.
Why, oh why, oh why?
I was contacted by a mother from
the southern hemisphere who managed to get Bumetanide prescribed by a pediatrician,
based on Ben-Ari's earlier publications. The diuresis is proving a problem for her family, but the positive
effects are clear, for example her son now uses the word “Mummy”, but only
while taking Bumetanide. If you are a
Mum/Mom, that is a big deal. He also now responds to his own name and is "more present", the hallmark sign of a bumetanide-responder.
She saw me on YouTube and sent me a
long email, including the “why, oh why, oh why?” are more people not giving
bumetanide to their child with severe autism.
There is no good answer.
This Mum, now realizing she is not
alone, plans to continue Bumetanide therapy.
Good for her!
Who dares wins, or at least stands a chance
I was recently sent an email
version of an old post I had written on myelination. The sender had read it and
convinced her doctor to prescribe her son Clemastine.
Her son has a single gene autism
that is known to feature impaired myelination.
I pointed out that in my blog there
are many references to therapies shown to benefit different aspects of the
myelination process, clemastine is just one.
Some of these therapies are OTC, like alpha lipoic acid (ALA) and the
N-Acetyl glucosamine (NAG), that Tyler brought to everyone’s
attention.
Is the young man in question going to improve in function
taking one or all of these 3 therapies? At least the mother in question is
going to give them all a good shot.
Good for her.
Conclusion
I have received quite a few comments and messages about the
Bumetanide trial failure. Many are along
the lines of “what do we do now?” and “how long will we have to wait?”
It looks like it pays to be an early adopter, rather than having faith that clinical trials will be structured and implemented properly.
It has been suggested in the research that a large, 10g, daily dose of the OTC supplement TMG (trimethylglycine) may have an equivalent chloride lowering effect to bumetanide. There is only anecdotal evidence to support this, but it seems to work for our reader Nancy's adult son - good job Nancy! The other potentially chloride lowering drugs are more difficult to obtain than bumetanide itself.
There likely will never be a single unifying therapy for
autism, just like there can never be for cancer. In both conditions it is all about specific
sub-types.
You would think that the previous trial failures in autism would
have caused people to learn this important lesson.
Hopefully, in the future Suramin clinical trials, where two competing companies are using the same therapy, it will not be assumed that everyone must be a responder for the therapy to be valid. From the data, it does look like Suramin improves symptoms in a significant percentage of those with severe autism; but the same can also be said of Bumetanide, based on the earlier trials
In December Monty will commence his 10th year of Bumetanide therapy. We have made short breaks periodically to check it is still needed. For our case of autism, Professor Ben-Ari clearly got the science right and transformed a little boy's future life, something Ben-Ari can always be proud of.
