- Botox, it's the most popular
cosmetic treatment in the world,
maybe because it's a bit magical.
A few injections, facial muscles relax, wrinkles disappear.
This makes it a very addictive treatment.
So much so I would say most people have it once
end up having it regularly for life.
And you don't really wanna stop having it once you start.
But as you know, due to the coronavirus,
many of the cosmetic clinics are or have been closed.
Meaning that people have been missing out
on their treatment.
There's even been a meme going around about Kardashians
missing out on regular Botox treatments.
But you don't have to be a Kardashian
to miss out the effects of Botox treatments.
It will be quite devastating to have those wrinkles
that you are used to being gone, come back.
But there's something else that may be stopping us
from enjoying the wrinkle reducing effects of Botox.
And that's our immune system.
Our immune system is here to protect us from harm
from bugs from the outside world.
It produces antibodies in response to viruses
or bacteria toxins to protect us
by providing us with immunity from future attacks.
And since Botox is a bacterial toxin,
then is it possible that our immune system
will defend us from it.
Is it possible to build immunity to Botox?
This would be highly undesirable,
especially given the nature of Botox is to have it done
every three to four months.
But why is it that you may not have heard of this problem
of immunity before?
And why do so few practitioners worry about it?
Here's what makes it confusing.
It's rare for Botox not to work at all.
But it's not uncommon for it to work partially.
Maybe it worked, but not completely as expected.
If you've had Botox,
you probably have had this experience yourself.
Maybe there was just a little bit too much
facial movement afterwards,
or maybe it didn't work as well as it first did,
or didn't last as long when.
When this happened, I often blamed myself
rather than the Botox.
Maybe it was the positioning of the injections,
the depth, an inadequate dose.
It sort of reminds me of that episode of Seinfeld where
George gets out the, it's not you it's me routine.
- You're giving me the,
it's not you it's me routine.
I invented it's not you it's me.
- But I'll be the first to admit that despite
practicing cosmetic medicine for 15 years,
I've spent most of those years in denial myself
about the possibility that my patients
are becoming immune to Botox.
Until I came across a small handful of patients
who despite topping up their Botox,
despite doubling the dose,
despite multiple attempts at trying to get
their Botox to work, nothing happened.
It didn't work at all.
Their muscles fully contracted afterwards.
This woke me up to the fact that immunity to Botox
is a real problem.
Although the number of completely resistant patients
over 15 years, I could count on the fingers of one hand.
It made me think what about those
who are partially resistant.
The only way to know if you are developing
a degree of resistance or partial resistance
or immunity against Botox.
Is to do a blood test, to detect neutralizing antibodies.
The only place I could find it in the world to do this test
was a place in Germany called Toxogen.
I actually emailed them with
the view of sending them samples from my patients to test.
Financially it was very costly.
And the feasibility of sending blood up there was low
due to the fact that you needed cold storage transport.
So for those where the Botox isn't really working
as well as we expect,
we can't just do a test for the antibodies.
Well, not very easily from here in Australia anyway.
And as a whole,
we can't easily determine the percentage of patients
who develop neutralizing antibodies with Botox treatments
because of the difficulty of testing everybody.
That's why this study
of the formation of neutralizing antibodies
by professor Phillip Albrecht.
Done in Germany with access to the Toxogen labs
is a significant study.
And he showed that basically 13% of 596 patients
of those treated formed new neutralizing antibodies
against the botulinum toxin.
When used for neurological conditions,
such as blepharospasm, cervical dystonia,
facial hemispasm, spasticity, and dystonias.
There are some neurological conditions
used in the Albrecht study
that are very very similar to the cosmetic treatments
that we perform.
Blepharospasm or twitching of the eye muscle.
Very very similar to crows feet treatments for wrinkles
with similar dosing.
So it is likely that resistance is an issue
with cosmetic Botox,
as well as Botox for neurological concerns.
To unravel the underlying causes of immunity to Botox.
Let's look at the bacterial toxin more closely.
In Australia there are three brands of botulinum toxin,
two of the three brands Botox and Dysport
have not only the active part, the neurotoxin,
but also have an associated complexing protein,
which are not involved in the function
of the botulinum toxin itself.
With Botox and Dysport the complexing proteins
that come with it
are actually a risk factor for developing immunity.
They often trigger the immune system
leading to the formation of antibodies,
both to the complexing protein and the active neurotoxin
rendering the treatment ineffective.
But more recently over the past few years,
a third brand of botulinum toxin
has become available in Australia.
It is Xeomin it's purified,
and it does not complain complex in protein.
I've been fortunate enough to be able to talk to
the inventor of Xeomin Dr. Jürgen Frevert.
Scientist, and botulinum toxin expert,
who has a long experience with botulinum toxins,
his inventor of Xeomin
the purified botulinum toxic without complexing proteins.
So we're gonna ask him what the purpose of
the complexing proteins were,
and why they were contained
in certain botulinum toxin products.
And what are the advantages of having a botulinum toxin
without these complexing proteins?
So thank you Jürgen for being a part of this talk.
You're often nicknamed the godfather of Xeomin
that's because you're the inventor of Xeomin,
which is the botulinum toxin
which is purified free of complexing proteins.
Now maybe you could tell us a bit about
what led you to create this botulinum toxin.
- In 1990, I became a advisor consultant
with the company Allergan
Allergan was interested in my work
because I was a specialist
and I'm a specialist in botulinum toxin.
But at that time, and again,
didn't have much experience with proteins with biologicals.
So they approached me and I became a consultant.
And well, I learned that Botox is
based on botulinum toxin complex.
That means not only the active substance,
the neurotoxin is in Botox,
but a lot of different peculiar (indistinct) proteins
called the complexing protein.
- Why did they put them in there?
I mean, I don't understand this.
From my understanding it's not a necessary
part of the botulinum toxins.
It's not an active part.
Why are there these complexing proteins?
- To go a little bit back to the basics,
the Clostridium produce the botulinum toxin complex
for the special purpose.
Maybe you know that botulinum toxin is the food poison.
If you eat rotten meat for example, or vegetables,
which are contaminated with Clostridium botulinum,
you can get an intoxication.
But interestingly, botulinum toxin
you know that it's a protein.
And proteins like the proteins in the meat,
vegetables and so on.
They are degraded in the stomach and the intestine.
And that's why the Clostridium
so to speak invented the complexing proteins
to protect the neurotoxin against degradation
in the stomach and the intestine.
That's the reason why there is a botulinum toxin complex
for oral bioavailability.
But in a therapy,
the complexing proteins do not have any function
because what's working in
patients are injected into the muscle
what's working is the neurotoxin itself.
The neurotoxin is taken up by the nerve cells
and then inactivate, so to speak the nerve cells.
So they neutralize the nerve cells.
- The complexing proteins do nothing
in terms of the activity of botulinum toxins.
So my question to you is, if this is the case,
why has it taken us so long to get to this point where
manufacturers only now,
or only since you invented Xeomin only since then,
have we decided to make a purified toxin?
Why hasn't this been done from the beginning?
What do you think the reasons are.
- The thinking was that the complexing proteins
are necessarily for the stability of the neurotoxin.
It was thought that the neurotoxin
is a very lay by substance,
which is immediately degraded denatured after dilution,
after formulation, after drying.
And that's the reason why again Allergan
stick to this botulinum toxin complex.
And the other reason was that a good colleague of mine
from sort of speak from Allergan, mentioned that,
well, that a neurotoxin is too sticky.
It sticks to the wards of the vial or two tubes or syringes.
So the complexing proteins are necessary
to protect the neurotoxin against degradation
and against sticking.
But that was not my opinion.
I was pretty sure, I was convinced that it is possible
to develop neurotoxin with all the complexing proteins.
And in the end we found an optimal as you know,
formulation, which really stabilizes the neurotoxin.
So that Xeomin and that's the only product on the market.
Xeomin is stable at room temperature.
So it's really possible to develop
a neurotoxin without the complexing proteins.
The complexing proteins are absolutely useless.
- So when you created Xeomin
and you found that it didn't stick to the vial
it was stable.
Did you have to create that first or did you sort of know
already that it was going to be stable
and not stick to the vial
without these complexing proteins?
I mean, how did you envisage that?
- Well, this was of course my thinking,
I was an optimist so to speak,
I've worked with the neurotoxin and I thought well,
I know everything about the neurotoxin.
I was really convinced that I will develop
an optimal formulation for the protein
and prevent sticking and so on.
It was of course a speculation,
but in the end I was successful.
My optimism was justified so to speak.
- Amazing so really given that the other botulinum toxins
have protein,
but Xeomin is the only botulinum toxin without protein.
If that is the case and as doctors,
how can we sort of ethically justify giving
our patients a botulinum toxin with protein,
knowing that it will likely,
or have some chance of causing some degree of immunity?
What are your thoughts on that?
- From my thinking,
it's not really justified to inject complexing proteins,
which have no function in the mechanism of action.
Which have no function at all in the therapy
with botulinum toxin.
Why inject patients with unnecessary proteins,
which are not an advantage for the patient.
- Yeah, for sure.
And I understand that your,
from doing a bit of research about yourself,
I understand that you yourself have actually
vaccinated yourself against botulinum toxin.
- Exactly I'm vaccinated because that was required
by my employer when I started with botulinum toxin,
because I've worked with extremely high doses,
millions of units per Ml or per CC.
So it was requested that I became vaccinated
and I developed a very high titer.
And so look at my glabella nines,
you can inject 1,000 units, nothing will happen.
Because my antibodies they neutralize the units
which are injected into my (indistinct)
or procerus or wherever you inject.
- It goes to show that botulinum toxins,
it can act as a vaccine,
whether it be purposely or whether it'd be unintentionally,
like when we're treating a frown lines, forehead lines,
in the aesthetic field, for example.
- Exactly, and that was our thinking in the beginning.
And then I started with botulinum toxins,
the (indistinct).
We knew that at that time,
a lot of patients treated with Botox developed antibodies.
About 15 to 20% of the patients developed antibodies.
And so our thinking was well,
develop a pure neurotoxin.
So that would be,
would avoid prevent the development of antibodies
and in the end you'll be all right
until now there is no secondary non-response
due to antibody formation.
You know that when patients develop antibodies
neutralizing antibodies against the product.
It is not possible anymore to treat these patients
because the antibodies
grab so to speak the neurotoxin and prevent
the uptake of the neurotoxin by the nerve cells.
And so until now,
there is no secondary non responsible with patients
treated with Xeomin the pure neurotoxin.
- So to date,
what you're saying is there's no recorded cases
of non-responders from Xeomin
due to neutralizing antibodies.
No one's ever had a case.
- Exactly.
- Wow, that's phenomenal.
- The (indistinct) naive patients,
because some patients who are treated
with Botox or Dysport before,
they had developed antibodies against that.
- So once you develop antibodies
to one botulinum toxin,
Botox, or Dysport, for example.
Can you then go on to have Xeomin
and why will it work or not work?
- Well, the thing is that the antibodies,
the neutralizing antibodies are directed
against the neurotoxin
and the patients who have antibodies after treatment
of the Botox or Dysport antibodies against the neurotoxin,
the active substance.
- You'll be immune to all of them.
Once you immune to one you're immune to all of them
is what you're saying.
- Exactly, because the neurotoxin in Botox, Dysport,
and in Xeomin and all the other products,
the Type A neurotoxin is very similar.
Generally it is impossible to treat patients
who have developed antibodies.
You have to wait some time.
And there is a discussion how long you must wait
until the anybody titre decreases over time.
- So if someone does become immune to botulinum toxins
over the course of their treatment,
how long is the average time
before that neutralizing antibody titer drops?
What is your experience with that?
How long does someone have to wait
before it will start to work again?
- That is complicated to answer.
The reason for that is it depends on the,
on the concentration of the antibody.
So on the height of the titre.
If you have a high titer,
it takes a longer time until
the titre is low enough to inject.
If the patient only develops a small titre,
it takes a shorter time.
So there are a couple of publications
in cervical dystonia patients.
Some patients could be treated, but after two years,
some patients update in longer time.
The injection of Xeomin in patients who have developed
an antibody titer does not increase the antibody titre.
So it's safe to speak,
to test the zero influence on after six months for example.
- Without making it worse,
without making the antibody titers raise again, excellent.
I think that's all I need.
I'd like to thank you for your time.
Thanks for your knowledge,
for sharing your knowledge and your experience.
Maybe I'll see you at the next conference.
- Okay fine looking forward,
thank you very much it was my pleasure.
- Excellent, so unless you wanna have the occasional break
from your botulinum toxin treatment every once in a while,
it's better to use a botulinum toxin that is purified,
free of complexing proteins to help reduce your risk
of immunity to the treatment.
Because of need to repeat botulinum toxin in the longterm.
It's all about consistency
and about being able to count on the fact
that you can have your botulinum toxin treatment
and allow it to work for years or a lifetime.
We can't test for the presence of antibodies
or immunity easily.
So this is the reason why
prevention is much better than a cure.