For me, Bumetanide for Autism is now ten-year-old news, for us it has been working since 2012; the next interesting drugs in the pipeline include Suramin and Leucovorin.
It is extremely
difficult to trial Suramin at home, or indeed anywhere, and this makes it ever
more desirable to many parents.
Leucovorin
(calcium folinate) is easy to obtain; you can even buy liquid calcium folinate
from iHerb. You can find out pretty
quickly if it produces a profound benefit on your child’s type of autism.
I wish Dr
Frye and Professor Ramaekers good luck with the phase 3 trial of Leucovorin. It certainly works for our adult reader
Roger, but not for my 18 year old son, Monty.
Our reader SB’s child recently joined the group of confirmed responders.
After I
started writing this post, the results came in of a large (250 children) trial
of intranasal oxytocin. This trial
failed to show any benefit, over the placebo, in increasing
social behaviors in autistic children. As I have mentioned previously,
there is an inherent problem with intranasal oxytocin, the hormone has a very
short action, its half-life is 2-6 minutes. It would be much more effective to
provide a sustained release of oxytocin, which can indeed be achieved via
adding a specific bacterium to the gut. The other problem with intranasal
delivery is that you are not supposed to inhale the drug into your lungs, it
has to stay in upper part of your nose. How likely is it that parents/children
use the spray correctly? There is even a
special dispenser developed for drug delivery to the brain, but did they use
it?
In my trials of L. reuteri DSM
17938 it was obvious that the oxytocin
improved social behaviors, but I concluded that this was not such a big deal
and certainly was not a treatment priority. How would you assess the effect?
Very simple, you just count how many times your child is shaking boys’ hands and
kissing the girls. I don’t suppose that was the measurement that Duke
University used.
Many parents
do use Syntocinon nasal spray and this failed
trial does not mean they are imagining the effects. If I was them, I would try L. reuteri DSM 17938 and compare the effect and use
whichever is the most beneficial.
Suramin
Suramin is moving towards its Phase 3
clinical trials and, very unusually, two different companies are trying to
commercialize the same drug. One company
is PaxMedica and the other is Kuzani, who are ones that cooperate with Dr
Naviaux.
In the background is Bayer, the German
giant, who have been making Suramin for a hundred years as a therapy for African sleeping sickness and river blindness. We are told that making Suramin is quite
difficult, it is a large molecule; but if they could make it a century ago, how
difficult can it really be? The reality
appears to be that Bayer do not want to supply PaxMedica or Kuzani and so they
will have to figure out how to make it.
Suramin is sold as a research chemical, but there seem to be questions
about its purity. The very cheap Suramin
sold on the internet is very likely to be fake.
Today we will look at the data from
the South African trial carried out by PaxMedica and take a look at their
patent for their intranasal formulation.
We have heard very positive anecdotal
reports from the very small initial trials carried out by Professor Naviaux. Naviaux himself is very interesting, because
even though he is not an autism researcher, he is far more knowledgeable than
almost all of them on the subject of autism. If you read his papers, they show
a rare global understanding of the subject.
This “big picture” is what you need to understand such a heterogenous
condition as autism.
In the PaxMedica trial, 44 children
completed the trial, so that should be enough to tell us something insightful
about whether this drug is effective.
A recurring problem in all autism
trials is how well the placebo performs.
Here again in the Paxmedica data we have a very impressive blue line –
the placebo. It is just salt and water
and yet it is nearly as good as the trial drug (the orange line).
A big part of clinical trials is the statistics used to validate them.
Although I do have a mathematical background,
I believe in “seeing is believing”. The
data should be crying out to you what it means.
If it is so nuanced that it needs a statistician to prove the effect,
there likely is no effect.
In the above chart we want to see a
decreasing slope that would possibly level off as the drug achieved its maximum
effect.
What we see are two apparently
effective therapies, blue and orange.
The problem is that blue line is just
water, with a bit of salt.
Show me the data
What we really want to see are results
of each of the 44 participants, not the average.
There are likely groups:
·
Super responders
·
Responders
·
Partial
responders
·
Non-responders
No statistician is needed.
The data from the Suramin trial needs
to be presented in the kind of form used in the stem cell trial below:-
Since many hundreds of different biological conditions can lead to an autism diagnosis, we really should not expect there to be any unifying therapy that works for everyone. Indeed, we should perhaps be suspicious of any therapy claimed to work for everyone.
We always get to hear about the
super-responders in anecdotal reports.
We heard great things about
Memantine/Namenda, but the phase 3 trial was a failure. We heard great things about Arbaclofen
(R-Baclofen), but the phase 3 trial failed. In Romania our reader Dragos is currently
seeing great benefits from the standard version of Baclofen (a mixture of R-Baclofen
and S-Baclofen).
My son is a super-responder to
Bumetanide, but I know that most people are not. However, when I came across
the “bumetanide has stopped” working phenomena, it became clear that the
situation is more complex than a single one-time evaluation. We know why
bumetanide can “stop working” and how to make it “start working again”. An increase in inflammatory cytokines from the
periphery (i.e. outside the brain) further increases the expression of NKCC1 in
the brain and negates the effect of bumetanide; reduce the inflammation and bumetanide
will start to work again.
Why does the
placebo always do well in autism trials?
The assessments used to measure outcome are all observational, they are not blood tests or MRI scans. They are highly subjective.
It has been suggested that just being
in an autism trial improves symptoms of autism.
The parents give more attention to the child and this then skews the
results.
My way round this problem in my n=1
trials was always to tell nobody about the new trial I was making and wait for
unprompted feedback. This works really
well.
Who chooses the
trial goal (the primary endpoint)?
I like the fact that in the Leucovorin trial the goal is speech. It is a very simple target and relatively easy to measure.
For Bumetanide, I did suggest to the
researchers that they used change in IQ as an endpoint. Nice and simple, start with kids with
IQ<70 and then recruit those who have a negative reaction (paradoxical
response) to Valium/diazepam. Then
expect an increase in measured IQ of 10 to 40 points. Then you would have a successful phase 3 trial.
In many previous trials that ultimately
failed, some people did see a benefit, but they were different benefits. I did get a reader telling me how great
Memantine (Namenda) had been for her child, when I asked why she told me that
it was the only therapy that had ever solved her child GI problems. That certainly was never considered as a
trial goal/endpoint.
In my trial of Pioglitazone, I read
the research about both the mechanism of action and the observed effects listed
in the phase 2 trial:
"improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale–Revised (RBS-R)."
I was targeting something entirely different. Based on the mechanism of action, specifically the reduction of the inflammatory cytokine IL-6, I expected a reduction in summertime raging. It worked exactly as hoped for. This is the second summer we have used it.
Our reader Sara’s initial assessment
of the effect of Pioglitazone is focused on the improvement in sleeping
patterns. This is great, assuming the
benefit is maintained, but it is an entirely different benefit.
Was the trial
drug actually taken?
I suspect in the bumetanide trial,
many parents did not give the trial drug every day, as per their instructions,
because the diuresis was too much bother.
I know from reader comments and emails that many parents stop giving
bumetanide, even though their child is a responder. Some schools refuse to allow bumetanide
because of the disruption caused by frequent toilet breaks.
Because Suramin is given once a month
by infusion, there is 100% certainty that the drug or placebo was actually
taken. This is a big plus.
Was the intranasal oxytocin correctly administered
in the recent trial? I doubt it.
The problem with Leucovorin is that in
a minority of children is causes aggression, even if you follow Prof Ramaeker’s
advice and very slowly increase the dosage.
In the phase 3 trial parents should be informed of this possibility and
told to report it and be invited to withdraw from the trial. If they just stop the therapy to halt the
aggression, but their data remains included in the study, the results are
invalidated.
Intranasal
Suramin
Patents are often a good source of information and they do also tell you something about the people who wrote them.
Here below is PaxMedica's patent for intranasal suramin:-
Compositions and methods for treating central nervous system disorders
These results demonstrate that an antipurinergic agent such as suramin can be delivered intranasally to achieve plasma and brain tissue levels and that variations in the brain tissue to plasma partitioning ratio can be observed. These results demonstrate that an antipurinergic agent such as suramin can be delivered to the brain of a mammal by intranasal (IN) administration.
The
following Table 1 provides the averaged accumulated amount, in mg, of suramin
that has penetrated as a function of time
But how can the accumulated
level after 6 hours be less than after 5 hours?
The results of the study are also shown graphically in FIG. 1 where the cumulative amount (mg) of drug permeated was plotted versus time in hours. These data demonstrate that Formulation B containing methyl β-cyclodextrin (methyl betadex) provides significantly better penetration, versus Formulations, A , C, and D in the tissue permeation assay. Also, as is seen from a comparison of Formulations A and D, having a higher drug concentration can be advantageous to increasing permeation.
Formulation
A - suramin hexa-sodium salt at 100 mg/mL in water (no excipients) Formulation
B - suramin hexa-sodium
salt at 100 mg/mL in water, with 40% methyl β-cyclodextrin (methyl betadex)
Formulation C - suramin hexa-sodium salt at 100 mg/mL in water, with 40% HP
(hydroxyl propyl) -cyclodextrin Formulation D - suramin hexa-sodium salt at 160 mg/mL in water (no
excipients)
FIG.
7 shows a plot comparing the total percentage of suramin in plasma in mice when
administered by intraperitoneal (IP) injection once weekly for 4 weeks (28
days), intranasally (IN) daily for 28 days, intranasally (IN) every other day
for 28 days, and intranasally (IN) once per week for 4 weeks (28 days).
FIG. 8 shows a plot comparing the total percentage of suramin in brain tissue in mice when administered by intraperitoneal (IP) injection once weekly for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once per week for 4 weeks (28 days).
Does anyone think the above chart makes any sense?
The mice were maintained in group
cages (6 mice per cage based on treatment group) in a controlled environment
(temperature: 2 1.5 ± 4.5 °C and relative humidity: 35-55%) under a standard
12-hour light/1 2-hour dark lighting cycle (lights on at 06:00). Mice were
accommodated to the research facility for approximately a week. Body weights of
all mice were recorded for health monitoring purposes.
The mice were divided into the
following 5 test groups, with 6 mice per group.
Group 1: Intraperitoneal (IP)
injection of suramin, 20 mg/kg, administered weekly to animals beginning at 9
weeks of age and continuing for four weeks (i.e. given at Age Weeks 9 , 10 , 11
and 12). The suramin was formulated in Normal saline solution.
Group 2 : Intraperitoneal (IP)
injection of saline, 5 mL/g, administered weekly to animals beginning at 9
weeks of age and continuing for four weeks (i.e. given at Age Weeks 9 , 10 , 11
and 12). This was a control group.
Group 3 : Intranasal (IN)
administration of a formulation, described below, of suramin, at a
concentration of 100 mg/mL x 6 mL per spray, administered as one
spray per nostril, one time per day, (interval of each application is
around 2 minutes to ensure absorption) for 28 days (total of 56 sprays over 28
day period) beginning at 9 weeks of age (i.e. given daily during Age Weeks 9 ,
10 , 11 and 12).
Group 4 : Intranasal (IN)
administration of a formulation, described below, of suramin, at a
concentration of 100 mg/mL x 6
mL per spray, administered as one spray per nostril, one time every
other day, for 28 days (total of 28 sprays over 28 day period) beginning at 9
weeks of age (i.e. given once every other day during Age Weeks 9 , 10, 11 and
12).
Group 5 : Intranasal (IN)
administration of a formulation, described below, of suramin, at a
concentration of 100 mg/mL x 6
ml_ per spray, administered as one spray per nostril, one time every
week, for 4 weeks (28 days) (total of 8 sprays over 28 day period) beginning at
9 weeks of age (i.e. given once weekly during Age Weeks 9 , 10 , 11 and 12).
This
question was posed to me:-
A
nasal spray in a human is about 0.1 ml, how do you give a tiny mouse 6 ml per
nostril? Even 0.6 ml looks implausible.
Conclusion
Will Suramin pass a phase 3 trial? I think if it is trialed on a random group of 400 young people with moderate or severe autism, it will very likely fail.
Professor
Naviaux believes Suramin may be a unifying therapy, one that works in all
autism. The results from the PaxMedica
study do not support this.
PaxMedica has the data showing the individual results. Are there super-responders? Are there non-responders? Does Suramin perhaps make some people's autism worse? All we can see is the average response, which is marginally better than the placebo; not what we expected after seeing the initial study.
Expecting
Suramin to work well for everyone is raising the bar too high. Try and identify markers for the responders
and super-responders and then limit the phase 3 trial to these people.
Is
intranasal delivery of Suramin going to achieve a therapeutic level inside the human brain? Hopefully yes, but it may not
work.
Is long term
use of Suramin going to be safe? Will it require ever-increasing doses? Nobody
knows, and note that safety was the original concern when Suramin’s use was
proposed by Naviaux.
Intranasal
administration has the best chance of being totally safe. Spend a little extra money on the clever dispenser
covered in this old post, that keeps 100% of the drug in the right place.
https://epiphanyasd.blogspot.com/2015/09/opn-300-oxytocin-and-autism.html
Maybe get
someone other than a lawyer, to proof read your patent.
