Who Pays the Piper? Off-Label or Polypill

It seems that autism is not the only “untreatable disease”, that does appear to be treatable.  At least twenty years ago, one apparently related condition was extensively treated off-label.  I am reading an intriguing book about the off-label treatment of Fibromyalgia in the 80s and 90s.

 

Off-label

In medical-speak “off-label” is when a drug is use for a purpose it was never actually approved for.  If you have straight forward diseases, you would never need to use a drug “off label”.

In some countries off-label prescribing by doctors is totally discouraged, in others, it is quite common.

The problem occurs when it comes to paying for expensive drugs and, of course, who is to blame if things go wrong.

Since many drug discoveries are actually stumbled upon by chance, off-label drug use is not as crazy as it may sound.

Socialized Healthcare, Private Insurance and Lawsuits

In the developed world, healthcare is provided either via some kind of private insurance as in the US, or it is via the State, as in Europe.  If your insurer is unwilling to pay for off-label treatments, you will not get them (unless you pay yourself).  In the UK, if the treatment is not endorsed by NICE (in effect, the State), you are not going to get it.  In the old days, the doctor might have been willing to try some off-label drugs, but now they are likely to be more worried about being struck of the medical register for malpractice, or, in the US, being sued.

So, all over the world off-label prescribing is getting rarer.  Certain states in the US are more liberal, Florida I believe is one.

Your healthcare is really in the hands of big brother; in general, this is not a bad thing.  If you have some rare, “untreatable” condition, then the problems start.  Even if you know what off-label drug you want, you will struggle to get it.  You will even struggle to get any unusual blood tests done.

In some countries the system is much more liberal.  If you want to measure potassium in your blood or maybe IGF-1 or serotonin, the process is akin to having your dry cleaning done.  You pay and it gets done.

 

Off-Label in the US

Before insurers tightening things up in the 1980s, doctors in the US seemingly were able to prescribe pretty much what they wanted.  If you read about some of the things prescribed for severer cases of Fibromyalgia, you would be amazed at the things they used (IVIG, Baclofen, Oxytocin etc.) and how the underlying principle was one of trial and error.

Due to the unusual position of osteopathic medicine in the US, where osteopaths have the same drug prescribing rights as medical doctors, there are many “alternative” doctors practising what they call “holistic medicine”.  Then there is a small army of DAN doctors, some of whom are medical doctors and some are not.  You also have a large number of chiropractors in the US; graduates of chiropractic schools receive the degree Doctor of Chiropractic (DC), as I was told by a reader of this blog, US  Chiropractors do not prescribe drugs, but they do treat kids with autism (I am not sure how).

So it looks like, while the golden days are over, off-label drug prescribing is alive and well in the US.

 

From Off-Label to On-Label

You would think that once an off-label therapy gets established, it would be able to transition to on-label, and become an accepted mainstream therapy.  This does not happen very often.  The doctors using off-label widely, are seen as quacks by some established doctors and by much of the public.  If they are treating unusual, hard to define conditions, it is hard to carry out controlled clinical trials, and nobody has an interest to pay for them anyway.

So, off-label tends to stay off-label and for most people, untreatable conditions remain untreatable.

Polypill

I am wary of my ideas being seen as risky, off-label, quack nonsense.  They certainly are off-label uses.

I think you should be able to transition from off-label to on-label.  If the disease is just a cluster of symptoms and pathologies, it will be hard to identify the sub-type for which the therapy is effective.  This applies to both autism and indeed fibromyalgia.

To move away from the very unscientific, and indeed wasteful, trial and error approach, you have to be able to use reliable biomarkers or diagnostic tests.  You would have to prove to a very cynical public, that you are not spouting nonsense.

Then faced with a therapy which can be shown effective consistently, albeit for a rare, very well defined, condition (based on blood tests etc.), there is no good reason why the therapy should not go on-label.

The question now with the Polypill is to be able to identify with >75% certainly for whom it will be effective.  I also need to understand, and indeed predict, when it might stop working.  This may sound very strange, but can happen.

Predicting when it might stop working, as well as suggesting what to do should that occur, makes things tricky. To do it perfectly you would really need the old school off-label doctor, and a vast amount of consultation time, that will not be available.

I live in a country where access to lab tests is very open and they are inexpensive, so I have come up with a testing strategy to accompany the Polypill, using tests that are inexpensive.

The idea of the tests is twofold; to identify the sub-group of children who will benefit from the Polypill therapy and to establish a baseline of markers to later understand any cases, should the Polypill “stop working”

Blood tests

·        IGF-1

·        Serotonin

·        Free T3

·        Cholesterol LDL & HDL

·        Histamine

·        Inflammatory markers CRP and   IL-6

·        Potassium

I would also use the TRH stimulation test, except it is not available where I live and requires several blood draws.  It shows central hypothyroidism to be common in autism (as it is, interestingly, in fibromyalgia).

I am expecting any loss in efficacy of the Polypill to be accompanied by a surge in histamine and/or the easy to measure inflammatory markers, C - reactive protein (CRP) and Interleukin-6.

The trials would take place in winter (no pollen) and would exclude people with food allergies, digestive disorders, IBD, IBS, pancreatic enzyme deficiency etc.  The trial would be exclusively for early onset autism, no regression.

People with seizures would be very welcome and might form a separate subgroup within the test; I expect the incidence of seizure and epilepsy to be reduced by the Polypill.

Having created a trial based on children with elevated IGF-1, Serotonin, Free T3 and Cholesterol, I would then continue to measure all the above indicators on a monthly basis.

Assessing Success

Since the Polypill has several active ingredients, I would expect a marked reduction in autistic behaviours, based on any established autism rating scale.  I would expect parents, teachers and therapists to be really impressed by the effect.

Using the above screening biomarkers to select the trial group, I would hope to achieve a successful outcome in a great majority of cases.  This success rate has to be measured.  Perhaps the screening exclusions and biomarkers are too restrictive, or not restrictive enough.  If it was 100% effective, they should be relaxed; if it was 50% they should be tightened.

What intrigues me are the cases where the Polypill may stop working after a period of success.  If this is understood, it will be another step in understanding the dynamic nature of autism.  If the loss in effect can be correlated to an increase in histamine, in some cases, I will know what to do.  If in some cases CRP and IL-6 rise but histamine and serotonin do not, we would know that the immune system had been activated, but mast cells have not degranulated.  In these cases it would require the, currently under development, “Autism Toolkit”, to provide some immuno-modulatory therapy.

Just as abruptly as the Polypill might stop working in a child, I expect it will start working again, when the external stimulation (whatever it might be) has been withdrawn.

In children who have a permanent state of over-activation of their immune system, they should have sky high CRP and IL-6 and the Polypill will never start to work in the first place.  High inflammatory markers are seen in regressive autism, according to Ashwood, who is on my Dean’s List.

EMA

Having rationalised my objectives, I am finalizing my initial submission to the European Medicines Agency, to see whether the Polypill should remain Peter’s off-label curiosity, or become an Orphan Drug, to share with others.

 

 

 

Updated Conceptual Map of Behavioural Homeostasis in Autism

Ten months ago I decided to invent my own, admittedly subjective, autism scale to map the progress of Monty, aged 10 with ASD; a lot has changed since then, so I decided to update it.

For background to the scale, read the earlier post.

Conceptual Map of Behavioural Homeostasis in Autism

 

 

 

The chart above is an update of the original; I added the bright yellow line to reflect events since April 2013 and a future prediction.  I decided that predicting more than three years is pointless.

The orange line shows that autism was very present from birth, with a second wave hitting causing more symptoms and then a nice shallow decline.  Aged 8 and half, emotional stress causes a huge regression and he enters into the world of SIB and aggression.  The situation is gradually recovered using exclusively an ABA approach.  The new homeostasis is at a higher plateau.  I expect some epigenetic change occurred.

At 17 December 2013, we switch to the red line; this is the point when he started taking Bumetanide (BU), courtesy of Ben-Ari and Lemmonier, and then we see a sharp step change in improvement.  This was followed shortly thereafter by another step down, following the start of NAC.  This takes us to April 2013.  Now we switch to the yellow line.

In April 2013, 10 months ago, I started to look for further help in the form of "agent X".  I gave myself a year to find it, but it came much faster; statin therapy had arrived.

Come summer, everything goes sharply into reverse, with a big spike in the yellow line back up into the danger zone.  The spike seems to have been caused by over-activation of the immune system caused by pollen, of all things.  Using mast cell stabilizers the situation was fully recovered.  There was no net loss (no epigenetic damage).

Then in January, the experimental Polypill takes shape and we see another sharp drop in the autism rating on the yellow line.

Now we are on the verge of “nerd cloud”, which separates kids with serious autism from the regular kids below it.  The top end of the cloud might be called high functioning autism and the lower part Asperger’s.  When I was a child this cloud existed, but people were just called odd or weird; in the US they were already called nerds.  In 1950 the word nerd was created by Dr Seuss, in his book, If I Ran the Zoo.

It is of course a pejorative term, but nowadays there are some very successful and wealthy nerds, so maybe it should not be.

Time will tell whether we can continue to descend through the nerd cloud.  What is going to happen in a few months when the pollen returns?  Will the Polypill be mightier than the re-activated immune system?  Perhaps mast cell stabilizers should be in the Polypill?

 
It is clear that more work is going to be needed and, perhaps, in addition to an Autism Polypill, there is a need for an Autism Toolkit.  The Toolkit is what you need when the Polypill stops working, and perhaps, before it can start working in some people.

 

The over-activated Immune System in Autism or “why has NAC stopped working?”

 Organs of the Immune System

 Today’s post will combine some first class science from MGH (Massachusetts General Hospital) with some feedback that I have been receiving.

I have been receiving comments from parents who have tried some of the various new scientifically-based drug therapies for autism.  For some parents, none of them work.  This is not a surprise, since we have established that “autism” is just a general term for a collection of behavioral symptoms.  These symptoms can be caused by a remarkable variety of different factors and so a therapy can only be successful, if it is matched to the appropriate subject.  The lack of biomarkers currently makes it a case of trial and error.

What really draws my attention is when a successful therapy appears to “stop working”.  This has already happened to my son and it just happened to a reader of this blog; “NAC has stopped working”.

So I applied myself to figuring this out.  In fact, it is quite simple.  Here again we can learn from the comorbidities.  Asthma is another, sometimes nasty, auto-immune inflammatory condition.  Asthma often has flare-ups, but they are often quite predictable - icy cold air in winter and pollen in summer.  Most asthma sufferers in developed countries are very well cared for, and their medication is varied according to the magnitude of their symptoms.  A severe asthma attack may result in a visit to the nearest hospital and treatment with potent steroids, but the science is well understood.

When well-targeted, the current autism drugs can work reasonably well in treating the autism of “stable” subjects; just as a low dose of inhaled corticosteroid usually controls my son’s asthma.  However, when an external factor comes along and over activates the immune system, the medication is overwhelmed.  In asthma you would hear wheezing and have to make frequent use of a “rescue” inhaler like Ventolin and if that was overwhelmed, it would be a case of a nebulizer or an oral steroid, at home, or in hospital.

Unfortunately, you cannot call your doctor and say “my autism drug has stopped working”; he would not believe it worked in the first place.

Having been able to treat autism, it is quite a shock to see all those gains evaporate.  Fortunately, help is at hand in the scientific literature.  In the case of Monty, aged 10 with ASD, the problem was caused by something as simple as pollen.  The pollen triggered the “degranulation” of so-called mast cells that released histamine, serotonin and a whole host of inflammatory cytokines into the blood.  This results in the immune system being in a state of “over-activation”.  This takes the body back to the days in which such over-activation caused the damage that led to the child’s autism.

If I had the resources of the Massachusetts General Hospital (MGH), I would simply establish a base-line of inflammatory markers, like IL-6, for each subject; then, when the subject’s drugs “stopped working” I would measure them again.

Having recently come across a clever Italian called Alessio Fasano, a doctor specialized in Celiac Disease at MGH; I would also test serum Zonulin levels.  Now, Zonulin may sound like something out of Star Trek, and it has only a tiny entry in Wikipedia, but it is possibly the holy grail for those involved in the Gluten and Casein free diet.

Zonulin is a protein that controls the permeability of the gut (digestive tract).  It is also measurable and is indeed a very good indicator of who has a “leaky gut”.  According to Fasano, a leaky gut is a precondition for autism.  No leaky gut, no autism possible.

Now you might be thinking that this talk of leaky guts will then lead me to make crazy claims linking the gut to the brain and then to autism.  Well I am not going to make any such claims; I will leave the highly respected doctor from MGH to do that for me.

There are two videos.  The autism one is over an hour long, but is only a couple of weeks old.  The alternative film is much shorter, but is talking more generally about auto immune diseases.
 

Gut-brain interaction in Autism Spectrum Disorder

Then click on the film that looks like this:-

 

Or the short film:-

Unlocking the Connection Between Intestinal Permeability and Autoimmune Disease

 

Conclusion

This is all very interesting and clearly permeability of the gut looks like a big factor in some people’s day-to-day autism.  It may very well also be a factor in those “flare-ups”, which cause the immune system to “cancel out” the effects of otherwise effective autism drugs.  You may have noted in some of the more shocking autism news stories, that can even end in murder/suicide, ulcerative colitis had developed in the intestines of the autistic person, leading to a severe deterioration in behaviour, that then became unbearable for the carers.

Dr Fasano is a gastroenterologist and so has a lot to tell us about the gut, but some other areas are also involved. We also have the leaky blood brain barrier, a factor in other diseases like MS; a biomarker for that would also be handy.  We also have all the work on mast cell degranulation from Theoharides.  It just has to be fitted together.

So my advice to anyone whose “NAC has stopped working” is to look at what has re-activated your child’s immune system.  It might be Seasonal Autistic Mastocytosis, but it might very well be a related to Fasano’s leaky gut or at the extreme, some kind of colitis (Dr W’s autistic enterocolitis, perhaps).

Perhaps some of those children who do not respond to any of the current autism drugs are in a chronic state of immune system over-activation.  For them, no drug can help, unless the immune system is first re-set. (pass the prednisone or even some TSO; more on immunomodulation here)

 

 

Fibromyalgia, Autism and President Putin

 

I introduced Fibromyalgia in my last post; it is an neurological condition that can cause some very strange symptoms, in addition to pain and fatigue.  I imagine that there are various different underlying causes and so, like autism, it is really a family of disorders with overlapping symptoms.

Surprisingly, at least one type of Fibromyalgia would appear to have similar causes to classic autism, but its onset is after the brain has fully developed.  As with autism, the approved medical treatments are all for the symptoms, rather than the underlying condition.  The underlying condition seems to be a neuro-endocrine inflammatory disorder, sometimes with channelopathies.

One very interesting finding is that exercise consistently helps with the symptoms of Fibromyalgia.  I was reading a paper just last week that showed that exercise (jogging) reduced autistic behaviors.  It has already been well established that exercise is almost as effective as drugs at treating people with depression.

Here are some links:-

Can exercise improve behavior? Help encouraging a child who has autism

Exercise in fibromyalgia and related inflammatory disorders: Known effects and unknown chances.

 

Exercise may be Just as Effective as Medication for Treating Major Depression

So what is the wonderful power behind jogging or swimming, you might be wondering?  Exercise and even passively experiencing a roller-coaster, or motor bike ride, releases certain hormones in your brain, which causes a cascade of changes to many other hormones and neurotransmitters.  Depression, fibromyalgia and indeed autism all include some central hormone dysfunction; shaking up the homeostasis by exercise seems to do good.

I did look, a long time ago, for studies that showed precisely which hormones are affected.  The problem is that hormone levels in the blood do not tell you the hormone levels in the brain; if they did, then there would be a lot of demand for neuro-endocrinologists.    The problem is the blood brain barrier  (BBB).

You can of course measure hormone levels in the spinal fluid, but I do not suppose many people would volunteer for such clinical trials.  As a result, any intervention in brain hormone levels is likely to be a hit and miss affair.  People have tried to do it, but unless you can measure the result scientifically, it will remain voodoo science.

Some expert autism physicians continue to maintain classic autism is not treatable; that would suggest to me, they have never tried.  You can very easily change brain homeostasis, but it might be for better or might be for worse - but you can certainly change it.  Even if you make it worse, you know that you have been able to change it; then it is just a matter of rethinking and trying again.  As a patient, you naturally expect the specialist to get it right with 90+% certainty.  Without being able to measure hormone levels in the brain, it is rather like target shooting, while wearing a blindfold.  Maybe there are some safe interventions that will work in everyone.  I prefer to limit this blog to things I can prove scientifically, so I will keep the rest for my polypill.

For the risk averse amongst you, I suggest you rely on exercise.  Unless you are completely unfit, it seems that exercise can only do good.  You will never know which hormone levels changed, or what neurotransmitter did what, but then you do not need to know.

President Putin

Monty, aged 10 with ASD, has an elder brother Ted, aged 13.  Ted loves history and is also learning Russian; he very much wants to go to visit Moscow and also Putin’s home town of St Petersburg.  Given the choice, he would undoubtedly go to Izhevsk , a city in the western Urals, home of the Kalashnikov factory and museum.

Ted was very impressed to hear Putin telling journalists in Sochi that he swims 1,000 metres every day.  Even the journalists were surprised, “every day?”; “yes, every day”.

So I told Ted, who does have some of the stranger symptoms of fibromyalgia, that I listed in my previous post, if Putin can swim 1,000 metres, then you can swim 500 metres every day.

Today was the first day of the new regime.


 

Fibromyalgia and, perhaps, What Happened to the Missing Females with Autism

This post is about a condition about Fibromyalgia, a condition that affects 2-4% of the population. It affects women eight times more often than men, but it does, bizarrely, appear to be related to autism and is seen by some as a comorbidity.  I would go further and suggest that perhaps I have stumbled upon the missing females with autism. 

When you look at all the proposed drugs and supplements, there is a 90% overlap between the two conditions, even things like low dose naltrexone and flavonoids, like quercetin, crop up.

As we have seen earlier in this blog, autism is a disease related to the auto-immune system and inflammatory pathways.  There are many other diseases with similar origins, one example being arthritis.  Fibromyalgia tends to get lumped together with arthritis.  Families with autism present tend to have higher levels of arthritis and there are even some overlapping therapies, such as vagus nerve stimulation.

Fibromyalgia caught my attention, because it seems to be uncannily closely related to autism, but there are some distinct differences.  Classic “full-on” fibromyalgia is a disease about pain, whereas in autism people tend to have a high pain threshold.  Nonetheless, if you Google “Fibromyalgia with Autism” you will find no shortage of people suffering from both and pondering a connection.

Comorbidities are interesting, because they can indicate possible new therapies.  The people researching fibromyalgia are not generally the same people as the autism researchers.  The underlying pathologies though are very likely overlapping, even though neither is fully understood.

Fibromyalgia is neither degenerative nor curable, but it is treatable.

Here is a link to an article by a US doctor who came to the same conclusion.  (The article itself is not great)

Symptoms of Fibromyalgia

We can split these into two categories, pain-related and pain-unrelated.  In the case of autism we should look at pain-unrelated, but in the case of relatives we should look at both.  You will probably be able to diagnose a non-autistic family member with symptoms of this syndrome.

 
Pain-related:-

·        Widespread muscle pain and joint pain, the effects of these symptoms varies from person to person and from day to day.  Many people have flare-ups.  There are specific pain areas, and these are shown below:

 

·        Long-term studies suggest that it is not progressive, it does not cause permanent damage to your muscles, bones, joints or organs.

 

Pain-unrelated:-

This is a long list and typically only some will apply to any one person:-

·        Cognitive dysfunction, such as:

o   Difficulty following directions when driving

o   Losing your train of thought in the middle of a sentence

o   Difficulty paying attention

o   Memory problems

o   Difficulty expressing ideas in words

·        Depression, anxiety, irritability,  overreaction, anger outbursts, unpredictable mood swings, phobias and personality changes

·        Difficulty swallowing

·        Headaches

·        Restless leg syndrome

·        Sensitivity to the cold, and/or having cold hands and feet

·        Palpitations

·        Chest pain and costochondritis    

·        Sensitivity to light and noise intolerance.

·        Clumsy walking, dropping things

·        Hair loss

Fibromyalgia vs autism

There are some other similarities/differences with autism.

·        It often takes years to get a diagnosis and some doctors do not believe the condition exists

·        There is a specialist doctor that should know about it – the Rheumatologist, although Neurologists sometimes get involved

·        It is not curable, but it is treatable

·        It is usually diagnosed on very subjective measures

·        A blood test does now exist in the US  - the FM/a test  

The firm with the blood test is called, interestingly, “Epigenetics”.  If you make a blood test for Fibromyalgia, there is a good chance that the same researchers could develop one for autism.  They are measuring the level of pro-inflammatory cytokines.

The test is expensive, about $750.  Who knows how accurate the result is; they claim 99%.

In the UK, the National Health Service maintains that no test for Fibromyalgia exists.

A Neuro-immuno-endocrine disorder

Evidence exists that fibromyalgia is a neuro-immuno-endocrine disorder. Elevations in substance P, IL-6 and IL-8 as well as corticotropin-releasing hormone have been found in the cerebral spinal fluid of fibromyalgia suffering individuals. Increased numbers of mast cell numbers have been found in skin biopsies of some individuals with fibromyalgia.

Theoharides, who I have quoted extensively in early post on mast cells and autism, appears here too:- 

Fibromyalgia--new concepts of pathogenesis and treatment.

Lucas HJ, Brauch CM, Settas L, Theoharides TC.

Abstract

Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression and skin sensitivity. There are no genetic or biochemical markers and patients often present with other comorbid diseases, such as migraines, interstitial cystitis and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased corticotropin-releasing hormone (CRH) and substance P (SP) in the CSF of FMS patients, as well as increased SP, IL-6 and IL-8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis is put forward that FMS is a neuro-immunoendocrine disorder where increased release of CRH and SP from neurons in specific muscle sites triggers local mast cells to release proinflammatory and neurosensitizing molecules. There is no curative treatment although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron, are helpful. Recent nutraceutical formulations containing the natural anti-inflammatory and mast cell inhibitory flavonoid quercetin hold promise since they can be used together with other treatment modalities.

Treatment

Classic treatment involves tricyclic antidepressants, which are actually very closely related to the early antihistamine drugs. 

Even though low brain serotonin is a feature of the disease, counter-intuitively, it has been found that serotonin-3 receptor antagonists are effective; this is the opposite of what was expected.  Tropisetron is a favoured antagonist, but there are several others.  Tropisetron is also a α₇-nicotinic receptor agonist, which you may recall, I highlighted as interesting in posts on the cholinergic system and autism.

Oral treatment of fibromyalgia with tropisetron given over 28 days: influence on functional and vegetative symptoms, psychometric parameters and pain.

This blog is about autism, so let us go back to a previous paper I looked at.

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

 

In that paper tropisetron is put forward as a potential autism treatment.

 

10.1.2 ᾳ7 nAChRs

It is possible to use ᾳ7 nAChR agonists to treat neuroinflammation in ASD. There is strong evidence that activation of the ᾳ7 nAChR expressed on monocytes and macrophage, by inhibiting NF-kappaB nuclear translocation, suppresses cytokine release by them, and that this cholinergic anti-inflammatory pathway that provides a bidirectional link between the nervous and immune system, inhibits the innate immune response. Hence, a reasonable case can be made for the use of ᾳ7 nAChR agonists to treat neuroinflammation in ASD.

A second candidate drug, Tropisetron is a partial agonist of the ᾳ7 nAChR. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. In a clinical trial with 33 schizophrenic patients administration of tropisetron, without placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. In mice, the early postnatal period represents a critical time window essential for brain development. The administration of tropisetron from postnatal days 2-12

(P2-P12) in mice did not induce significant cognitive, schizophrenia-like or emotional alterations in tropisetron-treated animals as compared to controls, when tested in multiple behavioral assays.

 

It is the non-conventional treatments that overlap with autism, things like GH, IGF-1 and low dose naltrexone etc.  The interesting therapies relate to treating the non-pain symptoms. There are many such therapies and some have been used for decades, one or two may be interesting for autism; they may indeed be more effective in autism that in fibromyalgia.  There is even an overlap with therapies I am already investigating.