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Showing posts with label Rett. Show all posts
Showing posts with label Rett. Show all posts

Wednesday, 18 December 2019

Will Anavex for “Autisms” be worth the wait and the price, compared to Russian OTC Afobazole?





US-Russia cooperation has long been possible in Space, but not so often in Medicine. NASA reportedly pays Russia $85 million per astronaut to go the International Space Station (ISS).  The US Space Shuttle program ended in 2011, leaving a Russian Soyuz rocket the only way to the ISS.


This post comes ahead of the dietary autism post, awaited by Tanya.  It really is just a brief follow-on from the previous post. I have only just come across Anavex, which does add weight to the first post on sigma-1R.
                                                                                                               
Hundreds of millions of dollars are being spent in the US to develop a safe sigma-1R agonist (Anavex 2-73). This drug is being trialed in various autisms (Rett, Fragile X and Angelman syndromes), Parkinson’s and Alzheimer’s.

In the last post I wrote about a cheap OTC anxiety drug from Russia, called Afobazole, that appears to be a safe sigma-1R agonist.  This drug has also recently been trialed in autism and Parkinson’s - the same targets as Anavex.

I did make the point in my original sigma-1 post that I am interested in existing therapies, rather than potential ones, so I did not include Anavex, or any other research drug, in that post. Anavex is nonetheless interesting, because their research studies further support the suggestion that targeting ER stress via sigma-1 is an interesting avenue to pursue.  

ERStress and Protein Misfolding in Autism (and IP3R again) and perhaps what to do about it - Activation of Sigma-1 Chaperone Activity by Afobazole?



Anavex is claiming precision medicine, but in fact sigma-1R agonists appear more like the opposite, at least in terms of who you target.  The majority of both common and rare neurological disorders look like they should benefit from reducing ER Stress (from whatever cause); it is a shared feature.  So it looks more like a shotgun approach; that is actually a good thing, if it were to drive the price down.

What is needed is an affordable, effective, mass market drug; not an ultra expensive pill just for Rett Syndrome and perhaps a different colour version for Angelman's Syndrome.

Which will prove effective - Anavex or Afobazole? Or perhaps neither.

Having already made the case for Soyuz in my earlier post, here is the case for NASA, and for those with NASA-sized budgets, courtesy of  https://www.anavex.com/





















Treatment with Anavex 2-73 was seen to improve motor skills, acoustic responses and visual acuity in a mouse model of Rett syndrome, supporting ongoing Phase 2 studies in patients.
Its use also helped to lessen abnormal movements and ease breathing in these mice, its researchers said.
Anavex 2-73 (blarcamesine) is an oral investigational therapy developed by Anavex Life Sciences that works by activating the sigma-1 receptor (S1R), a protein involved in the correct folding of other proteins.
S1R activation results in reduced toxic accumulation of misfolded proteins, as well as lesser dysfunction in mitochondria (a cell’s “powerhouse”), oxidative stress and neuroinflammation, all involved in Rett syndrome. (Oxidative stress is an imbalance between the production of free radicals — potentially harmful molecules associated with a number of diseases — and the generation of antioxidant defenses.)
Researchers at Anavex, assisted by PsychoGenics, evaluated the potential treatment’s specific effects on Rett symptoms in a validated mouse model.
They assessed motor function (balance, motor coordination, locomotion, and abnormal movements or stereotypies), sensory function (reflex responses to sound stimuli and visual clarity), and respiratory function.
Motor and sensory functions were assessed in younger mice, while visual acuity and breathing were measured in older animals.
Results showed that Anavex 2-73 significantly eased motor dysfunction, and deficits in acoustic and visual responses compared to mice given a placebo.
Anavex 2-73 also induced a significant reduction in two distinctive features of Rett syndrome found in these mice: hind-limb clasping (an abnormal posture comparable to hand stereotypies in people with Rett), and apnea (involuntary breath-holding) that is the most concerning breathing abnormality in Rett syndrome, the researchers said. These improvements were mainly dependent on treatment dose and duration.
“In conclusion, the data demonstrate that [Anavex 2-73] is effective in ameliorating multiple neurobehavioral phenotypes in [Rett] mice,” the researchers wrote. “In line with previous animal and human studies [in other neurodegenerative diseases], [Anavex 2-73] also showed a good safety profile,” they added.
These data served as a proof-of-concept for an ongoing safety and efficacy Phase 2 trial called RS-001 (NCT03758924, still enrolling) in the U.S., and for the Phase 2 AVATAR study (NCT03941444) in Australia. These trials together will evaluate Anavex 2-73 in up to 51 women with Rett syndrome.











Conclusion

It may be that Anavex is far superior to the cheap Afobazole. Like the space shuttle was far more advanced than the Soyuz. 

But what if the cheap Afobazole is quite good enough?  Like the cramped, but reliable Soyuz rocket.

Anavex/Afobazole will not cure any severe neurological condition, just improve it, so it will need to be part of a polytherapy. That means the patient will need to be able to afford multiple drugs, somehow.

Coming back to those autisms, what if your daughter has Rett Syndrome, or son has Fragile-X Syndrome ?  Wait a few years for Anavex and for someone else to pay for it? or make do with some cheap Afobazole?











Friday, 21 December 2018

Education and Autism


This blog mainly concerns personalized medicine, which is a therapy targeted to a specific person, or sub-group.  Personalized medicine can include drugs, OTC supplements, diets and, importantly, non-drug medical therapies like vagal nerve stimulation.  Some non-drug medical therapies were covered in previous posts and others will be covered in future posts.
The other part of the bigger puzzle can be called personalized education; anything from ABA to music therapy to what you do at school.
Eleven years ago, when starting with our first ABA consultant, just about his first question was “are you following any special diets or biomedical therapies”. He was clearly against such therapies, seeing them as a big distraction from the all-important ABA and Verbal Behavior (VB).  He did indeed have a point, you do have to focus your attention on multiple tasks and avoid being obsessed with vaccines, gluten or candida, as some people appear to be.
ABA does have its limits, as our first ABA consultant found with his own son. In the case of severe autism it may well help a lot, but it usually is not enough. Rather ironically this ABA consultant eventually came back to me years later to ask about personalized medicine.
Some people report terrible experiences with ABA and, if these are genuine, I think there must be some terrible ABA therapists out there. We had very positive experiences with ABA consultants and our home-trained therapists. 

Education
In the case of Monty, aged 15 with autism, he started with very personalized education and only much later, at 9 years old, did we add personalized medicine.
It is pretty clear than in cases of severe autism you need all the help you can get and so as to achieve a  relatively good life (the palm tree by the beach, in the above graphic); you need personalized education and personalized medicine.

Education of typical children
For some years I was a school governor at an international school and so I got to know many different teachers, different educational systems and curricula.
When schooling kids with autism the choice is normally between mainstream school, special school or home schooling. In some countries home schooling is illegal.
Mainstream schooling varies greatly from country to country. Most active autism parents seem to be North American and they likely do not realize how lucky they are to have a pretty easy school curriculum, which lends itself to less able learners.
In some other countries the standard of maths and science is very much higher and school is really geared up to benefit the most able. Anyone of average ability, or below, very often gets left behind.
The level of selection in schools is also important and highly variable. In some countries kids get separated at age of 10-12 into those who are expected to do well and becomes doctors/scientists/ lawyers and those who will end up with vocational training rather than a degree.
In other countries you get a genuine mix of abilities all the way up through high school.

Poor Learners
I had a visit recently from a friend of mine who runs an organisation in Austria that tries to attract top achievers from university to spend two or more years teaching in the country’s worst performing schools, before starting their intended high-flying careers. It is part of an international group doing the same thing across the world. They seem to be doing well and the schools perform much better with their energetic young teachers.
What was interesting to hear was just how bad the standards are at some of these schools.  A significant minority of 12 years old kids are functionally illiterate. One reason is that they have many immigrant children who do not speak German at home, did not speak German in Kindergarten and now sit in a class that is 80% non-native German speakers. The end result is that they cannot write a sentence in German, even though they might have lived all their life in Austria. So much for inclusion/integration.
Interestingly, my friend told me that in Austria, almost no one knows that Hans Asperger was an Austrian.  I did not mention that some Americans are worrying about whether Asperger was a Nazi.  Andreas Rett, another Viennese doctor, whose name was given to Rett syndrome by the English-speaking world 17 years after he described it in the German literature, is another forgotten Austrian. Rett actually was a Nazi, so I suppose some people will want to rename that syndrome, when they figure this out. Leo Kanner was really Austro-Hungarian, being born in Lviv. Kanner was Jewish, so definitely not a Nazi. So many Austrians connected to autism and yet nowadays the German speaking world contributes almost nothing to autism research. I will leave you to draw your own conclusions.


Back to education.
The top performers educationally are usually Singapore, where they practice old-fashioned education and Finland, where they follow a very enlightened non-pressurizing Scandinavian approach and where school starts at 7 years old.

The maths curriculum and the workbooks from Singapore are widely used by home schoolers around the world and I bought them for my son. 

A suitable learning environment for someone with severe autism
In many developed countries education authorities believe that children with severe autism can be educated in both mainstream classrooms or in special education.

Given just how variable mainstream education is, we should not expect consistent results. For some children inclusive education will work well and for others it might be a disaster.  A lot depends on what you are being included into and you have to be “includable”.
Small classes, with up to 12 kids, that include all abilities and only one special needs learner give the best chance of success, in my opinion.

Classes with 30 kids including 2+ special needs learners are a recipe for failure for all 30 kids.
Special education varies from large groups and a single teacher in some countries to tiny groups and where each child also has their own 1:1 assistant. There is no normal or typical special school.  There are some very good special schools in the United States, but they must cost someone $100,000 a year.

Home schooling is only as effective as how good the “teacher” is.
Parents need to think long and hard about how to educate their child with severe autism and not assume the State will provide them a perfect solution.  The better the education is for typical children, the greater chance you have of good special needs provision. Not surprisingly, special education is good in Scandinavia and terrible in most poor countries.  One of Monty's assistants moved to Norway to be a special needs teacher.

Some people with severe autism will struggle to learn anything, anywhere. These people need personalized medicine or else their 15-18 years spent in “education” is just day-care and a prelude to institutionalization, perhaps with a nice name like a group home.                                      

Personalized Education combined with Personalized Medicine
At the age of 8, after 4 years of intensive ABA-inspired intervention, Monty could not grasp the simplest elements of maths; I mean single digit addition or subtraction using the number line. Language and cognitive function appeared to be immovable barriers to progress.

December 2018 marks six years after starting personalized medicine, and I just learned that Monty’s grade for Maths this term is B+. He could handle the algebra and trigonometry in the end of term test, without any prompting from his assistant.
The addition of personalized medicine has had a transformative effect on cognition.  This continues to surprise people even now. 

Equally encouraging is that Monty has taught himself to swim "properly", he has long been confident in a pool or in the sea, but now at school they go to swim in a full sized pool and get timed swimming laps. Today he was the fastest of two combined classes, that is something else that would not have been expected. 

One autism Grandad we know regards Monty as "80% fixed", but "some problems will always remain"; that is quite a nice summary. It is all relative to what you know, this Grandad only knows really severe autism.  I think many of the parents of the 1 in 40 now diagnosed in the US with "autism" would regard Monty as far from "fixed", but then their kids are fully verbal and have few challenges.  

People with severe autism inevitably plateau at a low cognitive-equivalent age, but it does not have to be like that, if you can treat the underlying biology.  
If you start by treating the biology and fine-tune brain function to the extent that is possible, then you should benefit greatly from all that costly personalized education, that you may or may not get someone else to pay for.

Conclusion
If you have a child with severe autism, life may become a huge challenge. There are all kinds of horror stories you can read about - I suggest you do not dwell on them.  Everyone has options, whether to rely entirely on what you get for free from the State, or whether to apply other methods.

In a resource unconstrained situation, the best outcome is likely to come by combining personalized medicine with personalized education. I can only say that this combination has worked well for us.  In terms of money, it has clearly cost much more than having a typical child, about twice as much. 

If money is tight, start with personalized medicine.
People tend not to put a value on time, but for many time may be the greatest cost. You typically cannot leave a person with severe autism unattended and if they have a complicated schedule, somebody always has to be there and to be able to step in when something gets cancelled, or someone is off sick. 

Until the 1970s, medicine did have a strategy for people with severe autism. It was diagnose, institutionalize as a young child and forget. The Germans added their own variant to this.  Having shut down all the big residential hospitals for mental conditions, there is now often a big gap in provision.  Where do you put adult-sized people with severe autism?  It may not be a problem for those who are docile, but what about those who are not?