Our reader
Natasa brought to my attention various things recently; this included the fact
that intranasal delivery of Suramin for autism is being developed and the
repurposing of an old drug called Metyrosine for autism.
I also noted
a recent study that used a popular probiotic formerly called VSL#3, now called
Visbiome/Viviomixx. This is interesting because it found that autistic people
without GI dysfunction benefited. The
study had a high drop out rate and the improvement was not huge. Visbiome/Viviomixx
is pricey for a probiotic, but not the price of two Ferraris like Metyrosine.
Suramin
Nasal Spray - PAX 102
Suramin is
Dr Naviaux’s idea to treat autism and indeed several other conditions. Suramin
is an existing drug approved outside the USA and made by Bayer. Clearly Dr Naviaux’s new partner Paxmedica
was not able to make a deal with Bayer, so they have to figure out themselves
how to manufacture Suramin, which loses more time. The good news is that they are working on
intranasal delivery, the traditional way to delivery Suramin is by injection.
Research
showed that the effect of Suramin is lost after a few weeks, so quite frequent
injections would be needed. Intranasal
delivery has the advantage of avoiding injections and hopefully reduces the
side effects of Suramin.
https://www.paxmedica.com/pipeline
Metyrosine
Metyrosine
looks very interesting, until you see the price.
Metyrosine
is yet another old generic drug, from 40 years ago, that can be used to lower
blood pressure. It inhibits the enzyme tyrosine hydroxylase and, therefore, catecholamine synthesis,
which, as a consequence, depletes the levels of the catecholamines dopamine, adrenaline and noradrenaline in
the body.
Metyrosine
seems to have been forgotten about as a cheap hypertensive drug, but was
repositioned as an ultra-expensive drug for a rare condition called Pheochromocytoma (PHEO).
PHEO is a rare tumor of the adrenal gland; these tumors are capable
of producing and releasing massive amounts of catecholamines, metanephrines, or
methoxytyramine, which result in the most common symptoms, high blood pressure,
fast heart rate, and sweating.
Unfortunately, Metyrosine (brand name Demser) has
become one of the world’s most expensive drugs, costing up to $30,000 a month.
Old posts on catecholamines:-
Metyrosine
for Autism
The proposed
mechanism of action for the treatment of ASD is consistent with the assumption
that an imbalance exists between catecholaminergic systems and the modulators
of aminergic systems in the CNS and periphery.
Excess levels of nerve growth factor (NGF) and brain-derived NGF (BNGF),
which are released into the catecholamine synaptic cleft, can cause branching
and arborization of synaptic terminals, thus increasing the strength of
catecholaminergic neurotransmission. Because growth factors are a component in
these synapses, elevated levels of NGF and BNGF become chronic, along with
elevated levels of dopamine and other catecholamines from these hypertrophic
nerve terminals. The result may be a hypertrophy of the synaptic architecture,
resulting in a persistent imbalance between aminergic systems and their
offsets, which can lead to overstimulation of some CNS tracts and depletion of
others. Consequently, increased dopamine activity within the CNS and the gut is
associated with ASD, repetitive stereotyped behaviors, and defiant and anxiety
disorders. By reducing presynaptic
catecholamine synthesis, storage, and release, Metyrosine/L1-79 may reduce the
associated release of NGF and BNGF, rebalancing catecholaminergic mechanisms in
the brain, gut, mesentery, and elsewhere. These effects are not mimicked by
receptor-blocking agents that reduce postsynaptic depolarization without
addressing the underlying hypertrophic dendritic architecture. If this proposed mechanism of action in ASD
is correct, reduced catecholamine synthesis, storage, and release should improve
ASD symptoms. In the long term, reducing catecholamine release may enable the
hypertrophic sympathetic nervous system to regress to a homeostatic
configuration.
I
suppose to get a unique patent, the developer has decided to use a different
version of Metyrosine.
Their version, L1-79, is slightly
different to Metyrosine
Metyrosine is the L-isomer of
amethylparatyrosine.
L1-79 is a mixture of the L-isomer of
amethylparatyrosine and the D-isomer amethylparatyrosine.
Metyrosine is already an approved
agent, and the US Food and Drug Administration
guidance states that any stereoisomer of an approved agent can be
considered to be the same agent, so the developer can treat their drug L1-79 as
being an FDA approved drug (but not yet approved for autism as the use).
Effect of L1-79 on Core Symptoms of Autism Spectrum Disorder:
A Case Series
Purpose:
This study examines the effects of the tyrosine hydroxylase
inhibitor L1-79, a racemic formulation of a-methylparatyrosine, in patients
with autism spectrum disorder (ASD) in a prospective case series. The L-isomer
formulation of amethylparatyrosine, metyrosine, is approved for the management
of patients with pheochromocytoma.
Methods:
Six male and 2 female patients aged 2.75 to 24 years with ASD
were treated for 8 weeks at L1- 79 doses ranging from 90 to 400 mg thrice
daily. Assessments at weekly intervals included the Aberrant Behavior Checklist
eCommunity (ABC-C), Connor's Parent Rating Scale (CPRS), and Clinical Global
Impressions (CGI) scale. The Autism Diagnostic Observation Schedule (ADOS) was
administered at baseline and week 10. Findings: The ABC-C and CPRS scores
improved between baseline and end of study for 7 of 8 participants; most
participants' assessment scores decreased. At week 8, the CGI efficacy index
was 05 for 6 of 8 participants, indicating modest improvement with at least
partial resolution of symptoms and no medication adverse effects, and 09 for 2
participants, indicating minimal improvement and no change in status or care
needs, without adverse effects. The mean ADOS scores improved by 31% for 4 of
the 6 participants tested, with 1 patient experiencing a 47% improvement. Seven
of the 8 participants previously taking psychotropic medications were stable
without their legacy medications while receiving L1-79, and 1 patient resumed a
single legacy medication at a lower dose. Three adverse events were reported;
symptoms were mild and resolved without change in therapy.
Implications:
These results suggest L1-79 may be a tolerable and effective
treatment for the core symptoms of ASD, which must be confirmed with
double-blind studies.
The trial
was very small, but if you look at the results, half of the participants were
big-time responders.
If Metyrosine
was still a cheap antihypertensive drug it would be very interesting.
Unfortunately,
there is a clear trend to withdraw cheap generic drugs that can be repurposed
and then bring them back as ultra expensive drugs for the new use.
Sadly,
autism will need polytherapy, so you may need 5 drugs. Nobody can afford 5 ultra-expensive drugs.
Viviomixx/
Visbiome for those without GI dysfunction
Italians like probiotics and the study below is from
Italy. It uses the De Simone Formulation (DSF) which became well known as
VSL#3, but following legal disputes is now marketed as Vivomixx in EU,
Visbiome in USA.
The study does suggest that those
without any GI dysfunction may benefit from this product. These people are in the
“NGI group”, in the paper below.
We already know that some people with
autism and GI dysfunction do benefit from this product, which is widely used by
people with all kinds of GI dysfunction.
Clearly if you reduce GI dysfunction, behavior is likely to improve.
It is more potent than many probiotics.
Each packet contains 450 billions
bacteria from eight probiotic strains:
·
Streptococcus thermophilus
DSM24731
·
Bifidobacterium breve
DSM24732
·
Bifidobacterium longum
DSM24736
·
Bifidobacterium infantis
DSM24737
·
Lactobacillus acidophilus
DSM24735
·
Lactobacillus plantarum
DSM24730
·
Lactobacillus paracasei
DSM24733
·
Lactobacillus delbrueckii
ssp. bulgaricus DSM24734
The beneficial effect was there, but not
huge.
No differences between groups were detected on the primary
outcome measure, the Total Autism Diagnostic Observation Schedule - Calibrated
Severity Score (ADOS-CSS). An exploratory secondary analysis on
subgroups of children with or without Gastrointestinal Symptoms (GI group, n=
30; NGI group, n=55) revealed in the NGI group treated with probiotics a
significant decline in ADOS scores as compared to that in the placebo group,
with a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in Social-Affect
ADOS CSS over six months. In the GI group treated with probiotics we found
greater improvements in some GI symptoms, adaptive functioning, and sensory
profiles than in the GI group treated with placebo. These results suggest potentially positive effects
of probiotics on core autism symptoms in a subset of ASD children independent
of the specific intermediation of the probiotic effect on GI symptoms.
Further studies are warranted to replicate and extend these promising findings
on a wider
Viviomixx/Visbiome is one of the expensive probiotics,
but it is one of the serious ones. It looks like some people without GI issues
are likely to benefit to some degree. Is
it worth the expense? You would have to
try it.
We have seen case histories of people with autism, and
severe GI issues, greatly improving with VSL#3/ Viviomixx/Visbiome.
Effects of Probiotic
Supplementation on Gastrointestinal, Sensory and Core Symptoms in Autism
Spectrum Disorders: A Randomized Controlled Trial
Participants
were randomly assigned to probiotics (De Simone Formulation) (n=42) or placebo
(n=43) for six months. Sixty-three (74%) children completed the trial. No
differences between groups were detected on the primary outcome measure, the
Total Autism Diagnostic Observation Schedule - Calibrated Severity Score
(ADOS-CSS). An exploratory
secondary analysis on subgroups of children with or without Gastrointestinal
Symptoms (GI group, n= 30; NGI group, n=55) revealed in the NGI group treated
with probiotics a significant decline in ADOS scores as compared to that in the
placebo group, with a mean reduction of 0.81 in Total ADOS CSS and of
1.14 in Social-Affect ADOS CSS over six months.
In the GI
group treated with probiotics we found greater improvements in some GI
symptoms, adaptive functioning, and sensory profiles than in the GI group
treated with placebo. These results suggest potentially positive effects of
probiotics on core autism symptoms in a subset of ASD children independent of
the specific intermediation of the probiotic effect on GI symptoms. Further
studies are warranted to replicate and extend these promising findings on a
wider population with subsets of ASD patients which share targets of
intervention on the microbiota-gut-brain axis.
A novel and promising finding of our study is the
significant decline in ADOS CSS scores (both Total and Social-Affect scores) in
the NGI group treated with probiotics as opposed to those obtained in the
placebo group. This result, although deriving from a
secondary analysis, is particularly important from a clinical point of view,
especially in the light of the abovementioned psychometric properties of the
used tool. In fact, a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in
Social-Affect ADOS CSS over six months constitutes a clinically significant
decrease of ASD symptoms (34). Not all previous
trials with probiotics examined their effect taking into consideration the
presence/absence of GI symptoms (25). Our result suggests
that ASD children with and without GI symptoms could represent two different
populations and that probiotics interventions could potentially provide
different effects, likely due to distinct microbiota targets. Previous studies have already
suggested that differences in microbiome (45, 46) are independent
from GI dysfunction, and Luna et al. (45) argued that larger
and well-designed studies are still needed to determine whether microbial
composition may stratify ASD children beyond the GI symptoms. Within this
framework, a positive impact of probiotics on autism severity in children
without pre-existing GI symptoms supports the complexity of the
microbiota-gut-brain axis warranting further studies on this subgroup of ASD
subjects.
In the
subgroup of children with GI symptoms we found a positive effect of probiotics
not only on GI symptoms, but also on adaptive functioning, developmental
pathways, and multisensory processing, the latter now reported by the DSM-5 (1) among core symptoms
of ASD.
Taken
together, these different results on NGI and GI groups of children suggest that
the effects of probiotic supplementation in ASD children may be due to distinct
mechanisms. The well-known neurobiological heterogeneity of ASD implies that
each medication is likely to benefit only a subset within the spectrum of
affected children, as suggested by results of pharmacological trials in this
population (49, 50). The described
positive effect on both GI and NGI children paves the way for the
identification of those ASD subjects who can respond to probiotic
supplementation beyond the presence of GI symptoms, and even beyond GI
inflammatory status. In fact, in the current study, the supplementation with
DSF compared with placebo resulted in no significant effects on the levels of plasma
and fecal inflammatory biomarkers. In a previous investigation, we have
reported that the values of these biomarkers were in the normal range already
at baseline (51); thus, we do not
confirm the two previous studies (52, 53) reporting some
positive effects of probiotics on biomarkers of inflammation, and we could
hypothesize that the effect of probiotics on adaptative functioning is not
mediated by a reduction in systemic or intestinal inflammation.
Efficacy:
Secondary Exploratory Analyses on GI and NGI Parallel Arms
One of the original aims of this study was to
evaluate the effects of probiotics on ASD core symptoms, GI symptoms, and
plasma and fecal inflammatory biomarkers in ASD children with and without GI
symptoms. For this purpose the randomization was made independently in the GI
and NGI groups, to obtain four parallel arms. At the end of recruitment, the
sample size of each arm did not reach the target already determined for the
whole sample; the GI group, already less numerous, was also affected by a
bigger drop-out rate than the NGI one. Therefore, secondary exploratory
analyses among subgroups were performed. The four parallel arms were well
balanced for the total number of hours of rehabilitative treatments (GI placebo:
175± 91, GI Probiotic 156 ± 68, NGI placebo 134± 84, NGI probiotic 137 ± 129
p>0.05 for all the comparisons).
In the NGI group we found a significant
decrease both in the primary outcome measure, Total ADOS-CSS scores (which
decreased from 6.72 to 5.91 in the probiotic group and increased from 6.96 to
7.17 in the placebo group; mean change probiotic vs placebo, - 0.81 vs + 0.21
[95%CI, -0.76 to +0.20]; P = 0.026), and in Social-Affect ADOS-CSS (mean change
probiotic vs placebo -1.14 vs -0.04 [95%CI, -1.01 to +0.06]; P = 0.027).
In the GI group, statistically significant
effects were found in GI symptoms (Total GSI, Total 6-GSI, stool smell and
flatulence mean scores), and in adaptive functioning (Receptive Skills,
Domestic Skills and Coping Skills VABS-II subscales) for which probiotic
therapy was associated with greater improvements than placebo (Table 3). In addition, in the GI group a
significantly higher proportion of children in the probiotic group than in
placebo group showed a normalization of Sensory Profile scores in the
Multisensory Processing subscale (p= 0.013): the scores improved in 87% vs 28%,
respectively, and got worse in 0% vs 42%, respectively (Tables S4, S5).
Several limitations must be noted. Firstly, the large
dropout rates, although satisfactory considering the
duration of the study, may have affected the trial’s ability to reliably detect
significant differences between the two main treatment groups. This seems to
have affected particularly the subjects within the GI group, in which almost half of participants
dropped out, mostly in the placebo group (as reported in Figure 1). We
could speculate that parents of these children had more expectations about the
efficacy of the probiotic supplementation on GI symptoms than parents of
children within the NGI group. For this reason, they could be disappointed when
the treatment (or placebo) was not fully effective on GI symptoms of their
children, dropping out of the trial without waiting for its possibile positive
effects on core and developmental symptoms. Consequently, children who dropped
out were substantially comparable to children who completed the trial in all
clinical variables, with the exception of higher levels of GI symptoms. This
discrepancy between the two groups could impact the study’s ability to detect
other possible significant differences in the whole spectrum of GI symptoms. A
second limit is that the use of the ADOS-CSS evaluation as an outcome measure
in clinical trials has been recently disputed (43),
mostly because it lacks sensitivity to detect changes in short time periods.
In conclusion, a
six-month probiotic supplementation did not result in statistically significant
changes in autism symptoms in the whole sample of ASD preschoolers.
Nevertheless, for the
first time at our knowledge, we have observed in children without GI symptoms
treated with probiotics significant modification of core ASD symptoms measured
by the ADOS-CSS scores (specifically Social-Affect domain) that are unrelated
to the specific intermediation of the probiotic effect on GI symptoms.
As far as children with GI symptoms, the six-month supplementation with DSF
showed significant effects, when compared to placebo, in improving not only GI
symptoms but also multisensory processing and adaptive functioning.
All these findings could pave the way for further studies on
larger subgroups of ASD with the aim of improving precision medicine in ASD.
Conclusion
I am a big fan of affordable drug therapy.
There are some extremely clever one-off therapies that
cost more than $1 million. That seems OK,
you give it to a baby who then may go on to have a normal life, but someone has to
pay.
A $2.1 Million Drug for a Deadly Childhood Disease Is
Approved by FDA
A
potential cure for a lethal childhood disorder -- the first of its kind in the
U.S. -- is hitting the market at a cost of $2.1 million, paving the way for
more therapies that bring dramatic benefits for patients, along with challenges
for health-care systems.
The
U.S. Food and Drug Administration on Friday approved Novartis AG’s Zolgensma, a gene
therapy targeting children under two years old who have a severe illness called
spinal muscular atrophy. The Swiss drugmaker said it’s offering novel payment
options, including spreading out the costs over time, refunds for patients
whose treatment fails and discounts for insurers that provide swift coverage.
What looks
really unacceptable is repurposing a cheap existing approved drug and then
charging a King’s ransom for it.
It is very
expensive, and hugely risky, to develop a new drug, much less so to repurpose an old
one.
Repurposing
a cheap drug does cost money and somebody has to pay for this, and also the risk of
it not being successful.
All the
autism start-ups think they are entering a $2 billion a year market, but they
neglect the fact that people with severe autism will likely need
polytherapy. They think people will pay
$50,000 a year for a drug, but what if you really need 3 or 4 of these clever
drugs?
Take Knut’s
idea to repurpose Ponstan. This NSAID is
sold OTC in many countries for a few dollars.
Is it realistic to charge $50,000 for a slightly modified autism
version? In the case of Ponstan, this would be a preventative therapy for just a few years.
Metyrosine
was probably another three dollar drug, before it stopped being used. Now a one month supply costs $30,000.
