Transcript Non-invasive Vagus Nerve Stimulation for Treatment

Non-invasive Vagus Nerve Stimulation
for Treatment of Bronchoconstriction,
Migraine and Epilepsy
Bruce J. Simon, Ph.D.
VP Research
ElectroCore, LLC
Company Overview
•
ElectroCore® is a healthcare company focused on neuromodulation therapies.
•
The Company’s first three commercial products are for the treatment of:
•
Human respiratory disorders, including asthma, exercise-induced
bronchoconstriction (EIB), and COPD (AlphaCore®)
•
Primary headache in humans, including migraine and cluster headache
(GammaCore®)
•
Canine epilepsy (the GammaCore VET™)
•
The Company is currently in the early commercial phase within the EU and other key
countries for these first two products (IDE phase in the United States), and the early
commercial phase in the US for the animal health indication.
•
There are several additional therapies in pre-clinical development, including ones for
depression and anxiety, epilepsy, neuropathic pain, IBS and Alzheimer’s disease.
Vagus Nerve Stimulation
•
•
•
The vagus nerve has long been known to play an important role in the autonomic nervous
system
Cyberonics pioneered the use of electrical stimulation of the vagus nerve for the treatment
of epilepsy (FDA approved in 1997) and depression (FDA approved in 2005) using an
implantable device which required a surgical procedure
Physicians have attempted the treatment of a wide variety of other conditions using the
Cyberonics implantable device, including:
• Anxiety – George, et al., Brain Stimulation 2008 1, 112-21
• Alzheimer’s Disease – Sjogren, et al. 2002 J Clin Psychiatry, 63:11
• Migraine – Mauskop, et al., Cephalalgia, 2005, 25, 82-86
• Fibromyalgia – Lange, et al., Pain Medicine 2011, 12:1406-13
• Stroke – Mravec, Auton Neurosci, 2010 Dec 8;158(1-2):8-12.
• Obesity – Pardo, et al., Int J Obesity (Lond). 2007 Nov; 31(11):1756-59
We have developed a non-invasive way to stimulate the cervical vagus
nerve and shown that 2 minutes of stimulation can have an effect that
lasts up to 8 hours in animal and clinical models of bronchonstriction,
migraine and epilepsy
ElectroCore Development History
•
ElectroCore initially developed a VNS signal that could block a histamine-induced airway constriction
in guinea pig with direct to vagus stimulation. The effect was mediated by stimulation of low
threshold, afferent A fibers and not the efferent, high threshold C fibers which cause classic vagallymediated bronchoconstriction and bradycardia
•
The signal was shown to be effective in treating asthmatic patients reporting to the ED with
bronchospasm using a percutaneous electrode placed near the vagus nerve under ultrasound
guidance
•
A non-invasive stimulation technology (nVNS) was developed which could get a therapeutic signal to
the vagus nerve without stimulation of painful nociceptors. A 2 minute treatment produced a benefit
that lasted 4-8 hours
•
The signal was tested in a second ED asthma study and shown to be safe and effective
•
Treated asthma patients with migraines reported a significant decrease in migraine pain within
minutes of treatment
•
US IDE acute migraine study showed rapid pain relief with 2 hour results comparable to triptans with
no side effects. An EU study of cluster patients showed a 60% reduction in frequency and pain
•
In a rat chronic migraine model, a 2 min treatment reversed allodynia by inhibiting glutamate release
in the trigeminal nucleus caudalis (TNC)
•
The mechanisms of action in migraine and bronchoconstriction may involve up regulation of inhibitory
neurotransmitters (e.g. serotonin, GABA, NE) in the TNC and nucleus ambiguus, respectively
•
We are currently in RCT US IDE trials for cluster headache, chronic migraine and COPD, and RCT
European trials for cluster headache, chronic migraine, ED and home COPD treatment, EIB and IBS
•
Preliminary treatment of seizures in dogs in an open US study are encouraging.
Rationale for Treating Bronchoconstriction
with Electrical Stimulation
•
Asthma affects over 30 million people in the United States each year
and accounts for over 2 million ED visits, 1/2 million hospitalizations,
and over 4 thousand deaths each year
•
A large component of bronchoconstriction is due to a neurally mediated
smooth muscle contraction
•
The dominant neural pathways for controlling airway caliber are thought
to utilize oppositional controls in the parasympathetic nervous system
where cholinergic nerves mediate contraction and inhibitory, nonadrenergic, non-cholinergic (iNANC) nerves mediate relaxation
•
It was hypothesized that an electrical signal could be developed that
would:
– Block efferent vagal action potentials causing bronchoconstriction
Direct vagus nerve stimulation was optimized in a histamineinduced bronchoconstirction guinea pig model
5
Bronchoconstriction: Histamine Challenge
Dr. Charles Emala (Columbia Univ.), had developed a guinea pig model in which he used electricity to
cause bronchoconstriction.
Using the same model, direct to nerve vagal stimulation with a wholly different signal was found to
relieve bronchoconstriction in a histamine model in guinea pigs1
Tying off the nerve below stimulation did not block the effect, while tying off above did
Propranolol abolished the effect
Airway Pressure (cm H2O)
Control
Control
Stimulation
Stimulation
1. Hoffman, et al., Low voltage vagal nerve stimulation reduces bronchoconstriction in guinea pigs through catecholamine release,
Neuromodulation, 2012 May 2. doi: 10.1111/j.1525-1403.2012.00454.x.
6
Initial Human Studies – Airway Disease
Treatment
Control
50%
p=0.003
45%
Change from Baseline
•
Percutaneous Delivery Study
• 25 patient pilot study conducted in 5 emergency departments
• Patients failed 1 hour standard of care (SOC)
Non-Significant Risk (NSR) Study
• 76 matched control patients
• Patients failed 1 hour of SOC
FEV1
•
40%
35%
p=0.011
30%
25%
p=0.004
20%
15%
10%
5%
0%
0
10
20
30
TIme (min)
40
50
60
Is There a Better Way to
Stimulate the Vagus Nerve?
Many forms of energy have been shown to depolarize nerves:
1.
2.
3.
4.
5.
6.
7.
8.
Light
Heat
Mechanical
Ultrasound
Trans esophageal electrical stimulation*
Electric field induction by a time-varying vector potential*
Electric field induction by a time-varying magnetic field*
Transcutaneous electric field*
*These devices were built and tested
Trans Esophageal Stimulation Using an Inflatable
Balloon Electrode Attached to a Pediatric Nasogastric Tube
The vagus nerve runs between the esophagus and the trachea
Worked but some patients had a tendency to gag when the balloon was inflated!
9
Transcranial Magnetic Stimulation Device
Used for Peripheral Nerve Stimulation and Treating Depression
GammaCore and AlphaCore
•
ElectroCore developed several important breakthroughs in vagus nerve modulation:
–
–
–
–
A unique electrode configuration that produces a uniform electric field across the surface of
the electrode
A novel signal waveform that minimizes stimulation of skin pain nociceptors to allow for a
stronger signal that can reach the vagus nerve
Discovered that a 2 minute treatment can produce CNS effects that last up to 8 hours
Selectively stimulates low threshold, mylinated A afferent nerve fibers, and not the higher
threshold efferent C fibers responsible for bradycardia and bronchoconstriction
GammaCore
AlphaCore
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Comparison of nVNS with Percutaneous Stimulation
FEV1 Change from Baseline
•
Device
50%
Tested in an ED pilot study in S. Africa: Asthma patients who failed SOC were
treated with AlphaCore for 90 sec. and followed for 60 min. (Data compared with
previous ED study)
40%
30%
AlphaCore
Percutaneous
20%
Historical Control
10%
0%
0
15
30
45
60
Time (min) following stimulation
75
90
Spontaneous Headache Relief
From the South African ED Asthma Pilot Study:
“Subject is a 58 year-old female enrolled in the study and stimulated with the
AlphaCore™ on October 10, 2011 according to study protocol. The subject presented
to the emergency room with a previously diagnosed respiratory infection,
bronchospasms and headache. The subject underwent stimulation and exhibited
marked improvement in FEV1 and shortness of breath. The subject also reported
spontaneous relief of her headache following stimulation”.
From the US IDE Office-based Asthma Pilot Study:
Subsequent literature review revealed five publications showing reduction in
frequency and intensity of headaches with implanted VNS
Acute Migraine – US Pilot Study
•
30 episodic migraineurs were enrolled and instructed to treat 4 migraines as soon
as their migraine intensity reach moderate (2) or severe (3), but no later than 20
minutes after initial onset of pain
Data from 26 patients (79 migraines): 28% reached no pain by 2 hours and 58%
had mild or no pain, comparable to triptans
Effect of VNS with GammaCore on Headache Scores
2
Mean Headache Score
•
1.5
1
Baseline
5-Min
15-Min
30-Min
45-Min
Time following VNS
60-Min
90-Min
120-Min
Treatment of Cluster Headache with GammaCore
Data from the UK Open Label Cluster Headache trial (n=14) demonstrated greater
than 60% improvement in frequency and severity of attacks1. Seven patients
reported a significant or total reduction in their abortive treatments.
Reduction in Severity
10
Reduction in Frequency
3.5
9
3
8
2.5
7
6
2
5
1.5
4
3
1
2
0.5
1
0
0
pre-treatment
1Nesbitt
post-treatment
Pre-treatment
Post-treatment
et al. (2012). Non-invasive Vagus Nerve Stimulation for the Treatment of Cluster Headache:
A Case Series. EHMTIC, London
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Mechanism of Action
Bronchoconstriction
Parasympathetic MOA Summary
Parasympathetic Role: Afferent vagal A fiber activation, without simultaneous C
fiber activation, causes an increase in neuronal output from the nTS, which in turn
stimulates
•
The locus coeruleus1,2,4, resulting in elevated levels of norepinephrine5
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The dorsal raphe nucleus1,2 resulting in elevated levels of serotonin1,2,6
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The periaqueductal gray7, resulting in an increase in GABA3,7
All of which directly suppress activity in the Airway-related Vagal
Preganglionic Neurons (AVPNs) in the Nucleus Ambiguus
1Manta
S, Optimization of vagus nerve stimulation parameters using the firing activity of serotonin neurons in the rat dorsal raphe. Eur Neuropsychopharmacol. 2009.
19(4):250-255
2Dorr
and Debonnel. Effect of Vagus Nerve Stimulation on Serotonergic and Noradrenergic Transmission. 2006. J Pharmacol Exp Ther. 318(2):890-898.
3Ben-Menachem
4Groves
5Hassert
et al., Effects of vagus nerve stimulation on amino acids and other metabolites in the anaesthetized rat. 1995. Epilepsy Research 20:221–227
et al. 2005. Recordings from the rat locus coeruleus during acute vagal nerve stimulation in the anaesthetized rat. Neurosci. Lett., 379, 174–179.
et al. The Effects of Peripheral Vagal Nerve Stimulation at a Memory-Modulating Intensity on Norepinephrine Output in the Basolateral Amygdala. 2004.
Behav Neurosci 118:79–88.
6Hammond. 1992. Neurochemical effects of vagus nerve stimulation in humans. Brain Research 583:300–303.
7Prabha and Martin, Respir Physiol Neurobiol. 2010 . 173(3): 213–222
Parasympathetic Control of Airways
Airway-related Vagal
Preganglionic Neurons
Raphe
Nucleus
Periaqueductal
Gray
Locus
Coeruleus
Nucleus Tractus
Solitarius
Airway-related
Postganglionic Neurons
Unmylenated
C Fibers
Mylenated A
Fibers
Afferent Vagus Fibers
Efferent Vagus Fibers
Airway Smooth Muscle
Airway-related Vagal
Preganglionic Neurons
Raphe
Nucleus
Periaqueductal
Gray
Locus
Coeruleus
Nucleus Tractus
Solitarius
Airway-related
Postganglionic Neurons
Unmylenated
C Fibers
Mylenated A
Fibers
Afferent Vagus Fibers
Efferent Vagus Fibers
Airway Smooth Muscle
Noxious Stimulus
Increase in AVPN Firing
Glutamate (+)
Airway-related Vagal
Preganglionic Neurons
Raphe
Nucleus
Periaqueductal
Gray
Locus
Coeruleus
Nucleus Tractus
Solitarius
Vagal
Postganglionic Neurons
Unmylenated
C Fibers
Mylenated A
Fibers
Afferent Vagus Fibers
Efferent Vagus Fibers
Airway Smooth Muscle Contraction
Noxious Stimulus
Airway-related Vagal
Preganglionic Neurons
Raphe
Nucleus
Periaqueductal
Gray
Locus
Coeruleus
Nucleus Tractus
Solitarius
Airway-related
Postganglionic Neurons
Unmylenated
C Fibers
Mylenated A
Fibers
Afferent Vagus Fibers
Efferent Vagus Fibers
Airway Smooth Muscle
AlphaCore Stimulation
Decrease in AVPN Firing
X
Airway-related Vagal
Preganglionic Neurons
Serotonin (-)
(-) GABA
(-) Norepinephrine
X
Raphe
Nucleus
Periaqueductal
Gray
Locus
Coeruleus
Nucleus Tractus
Solitarius
Unmylenated
C Fibers
Airway-related
Postganglionic Neurons
Mylenated A
Fibers
Afferent Vagus Fibers
X
Efferent Vagus Fibers
Airway Smooth Muscle Relaxation
AlphaCore Stimulation
Conclusions
• AlphaCore provides a non-invasive, painless signal to the vagus nerve
which relieves acute bronchoconstriction and congestion in asthma and
COPD patients within seconds of treatment.
• Works when -agonists have failed
• Can replace albuterol as an asthma/COPD rescue medication
• Clinically significant increases in WOB, PEF and FEV1
• Patients may leave ED sooner
• Decreased use of drugs, reduced morbidity
• Decreased hospital admissions
The MOA may involve the inhibition of cholinergic outflow from AVPNs
to airway smooth muscle and mucus glands by release of GABA,
serotonin and norepinephrine from vagal afferent activation of the
periaqueductal gray, raphe nucleus and locus coeruleus, respectively.
23
Mechanism of Action
Primary Headache
Rat Chronic Migraine Model
Methods:
•
A rat model was developed to mimic the hypersensitivity seen in migraine
patients1
•
An inflammatory soup (histamine, serotonin, bradykinin and PGE2) was infused
onto the dura of awake rats 3x/week for 4 weeks until a long lasting increase in
trigeminal sensitivity was obtained
•
Trigeminal sensitivity was measured by a decrease in periorbital pressure
thresholds as determined by von Frey monofilament testing
•
Periorbital thresholds were measured before and after 1 minute of stimulation
with the GammaCore signal at 5 min, 30 min, 1.5, 2.5, 3.5 and 24 hr. post
stimulation
•
Thresholds were compared with untreated animals and Control animals that had
not been stimulated
•
In a second study, animals were injected with glyceryl trinitrate (GTN) an NO
donor that causes headaches in migraineurs, and levels of glutamate were
measured in the trigeminal nucleus caudalis (TNC).
1 Episodic dural stimulation in awake rats: A model for recurrent headache. Oshinsky et al. 2007. Headache 47(7):1026-36.
Results
•
Stimulation for 2 min with nVNS increases the trigeminal threshold to that of naïve animals. The effect
lasts for 3.5 hrs.
•
Treatment with the NO donor, glyceryl trinitrate (GTN) increases glutamate levels in sensitized rats (8x)
and naïve rats (2x) and causes a further 10-fold decrease in trigeminal thresholds in sensitized rats.
•
nVNS inhibits the increase in sensitized rats, reducing glutamate levels to that of naïve rats.
•
Ongoing studies will measure levels of the inhibitory neurotransmitters, serotonin, NE and GABA in the
TNC as a possible mechanism for the glutamate inhibition
Proportional Change From Baseline
10
9
8
nVNS+GTN - allodynic rats n=5
GTN only - allodynic rats n=5
GTN only - naive rats n=5
7
6
5
4
3
2
1
0
0
30
60
90
120
150
Time (min) after GTN
180
210
Parasympathetic Control of Migraine
Pain
Cortex
Perception of Pain
Is Blocked
X
Thalamus
X
Trigeminal Nucleus
Caudalis
Serotonin (+)
(-) Glutamate
Migraine Pain
Generators
(+) GABA
(+) Norepinephrine
Raphe
Nucleus
Locus
Coeruleus
Periaqueductal
Gray
Nucleus Tractus
Solitarius
GammaCore Stimulation
Afferent Vagus Fibers
Non-Invasive Vagus Nerve Stimulation
•
•
•
Provides rapid relief of bronchoconstriction in asthma and COPD patients
with 2 minutes of treatment
Decreases the frequency and severity of cluster, acute, chronic migraine
and other primary headache disorders
May be effective in treating other CNS disorders including anxiety,
Alzheimer’s disease, neuropathic pain, depression, IBS, stroke and obesity
• May normalize the underlying autonomic CNS dysfunction in these
disease states by modulating the expression of excitatory and
inhibitory neurotransmitter levels in the brain
Future Research
fMRI
fMRI
EEG
GSR, HRV,
Evoked Potential
30
Thank You
31
Probability of Successful Headache Treatment in
those Patients that Treated Four Headaches (65%)
0.5
Predicted Data
0.45
Actual Data
Probability of Success
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
0/4
1/4
2/4
3/4
4/4
Number of Successfully
Treated Headaches
P=.63 for these 52 headaches
32
Responder/Non-Responder Model
We therefore attempted to model the data assuming two groups of patients,
responders who have a high probability of successful headache treatment and nonresponders with low success probability.
The probability of successfully treating k headaches out of n is given by:
P(k,n) = n!/(k! . (n-k)!) . (NR . PRk . (1-PR)n-k + NN . PNk . (1-PN)n-k )
Where:
NR = Fraction of patients who are responders
NN = Fraction of patients who are non-responders = 1-NR
PR = Responder success probability
PN = Non-responder success probability
33
Probability of Successful Headache Treatment
0.5
Predicted Data
Probability of Success
0.45
0.4
Actual Data
0.35
Theoretical
0.3
0.25
0.2
0.15
0.1
0.05
0
0/4
1/4
2/4
3/4
4/4
Number of Successfully
Treated Headaches
65% Responders:
Probability of success = .92
35% Non-responders: Probability of success = .10
34
Responders and Non-responders
94% Success Rate in Responders
2.5
4
2
3.5
3
Pain Score
Number of Headaches
4.5
2.5
2
1.5
1
Baseline Score
120 min Score
1.5
1
0.5
0.5
0
0
0.25
0.5
0.75
1
1.25
1.5
1.75
2
2.25
Average Headache Pain Score at 120 min
2.5
0
Responders
Non-responders
Group Type
35
Non-Responders?
• Why might some patients be responders and others not?
• Biological differences in response to vagal stimulation
• Differences in underlying pathology of the migraine
• Active signal not getting to the vagus nerve due to anatomical differences
(e.g. deeper vagus in heavier patients), or insufficient stimulation
amplitude
A subset of patients (6 with 21 headaches) reported AE’s related to muscle
stimulation, suggesting an amplitude sufficient to provide therapy.
These subjects had a 90% success rate.
Can we improve the success rate with better patient training on the correct
use of the device?
36
Is Vagus Nerve Stimulation Safe?
• Stimulation of vagal efferent fibers has long been known to
cause bradycardia and bronchoconstriction
• A key breakthrough by ElectroCore was the discovery of a
way to stimulate only the low threshold afferent vagal fibers
and NOT the high threshold efferent fibers
High Voltage but NOT Low Voltage Induces
Bradycardia
Stimulation is effective at .5 – 1 V
3 Volts
10 Volts
Time (s)
Time (s)
Blood Pressure Tracings
High Voltage but NOT Low Voltage Induces
Bronchoconstriction
off
2v 10 sec
off
5v 20sec
off
10v 10 sec
off
15v 10sec
15.0
2 Volt
6 Volt
10 Volt
16 Volt
10.0
minutes
213.0
216.0
5.0
219.0
Time (min)
222.0
cm H2O
20.0
Airway Pressure
Airway Pressure (cm H20)
25.0
nVNS Has no Effect on Blood Pressure or Heart Rate in Humans
130
120
110
100
90
80
70
60
50
40
Mean BP
Systolic
Diastolic
0
15
30
45
60
75
90
120
110
Mean HR
100
90
80
70
60
50
40
0
15
30
45
60
75
Time (min) following stimulation
90