Metyrosine, Intranasal Suramin and Visbiome/Viviomixx for Autism?

 

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:-

Secondary Monoamine Neurotransmitter Disorders in Autism – Treatment with 5-HTP and levodopa/carbidopa?

Catecholamines and Autism

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.