Transcript Acute CINV (Day 1)

Leading The Development of
Transdermal Neuromodulation Technology
Company Overview
Neurowave Medical Technologies (NMT) was established in late
2006 with the acquisition of the neuromodulation division of
Abbott Laboratories.

NMT designs, develops, and manufactures advanced
transdermal neuromodulation devices for the treatment of a
wide range of acute and chronic conditions.

Robust Proprietary Transdermal Neuromodulation Technology
Platform Targeting at Multiple CNS & GI Regulated
Conditions

NMT’s mission is to develop products that can be used as
“First Line” and “Best in Class” options vs. current
pharmaceuticals

4 FDA Approved Indications Ready For Immediate
Commercialization worldwide (CINV, PONV, PINV , GNV)

Active Out-License/Partnering Strategy for Anti-Emetic
products & Pipeline Indications From Technology Platform
Developing Transdermal Products that have not only Proven Clinical Efficacy,
Limited Side Effects, but also Provide Economic Value for Patient & Providers
2
Table of Contents
Clinical Information
• Efficacy in CINV
• Safety
Device Technical Specifications
• Generation I
• Generation II
• Generation III
Mechanism of Action
• Overview
CLINICAL
INFORMATION
4
Clinical Highlights Across Indications
More than 23 articles published in peer reviewed US/European
medical journals for PONV, CINV and NVP patient populations:
Key findings include:
 Efficacy comparable to current “best in class” 5-HT3 RAs anti-emetics
 Significant improvement in efficacy when device + 5-HT3 RAs used in combination
(60%+ risk reduction vs. with Ondansetron or device alone)
 50-60% relative risk reduction when used as a first-line treatment compared to
gold standard of 25% risk reduction
 Significant reduction in total anti-emetic drug usage
 Significant Quality of Life (QOL) improvements for patients
 Significant improvement in patient satisfaction
 Safety profile results in reduction adverse events
Summary of CINV Clinical Studies (1 of 2)
•
Pearl ML, Fischer M, McCauley DL, et al. Transcutaneous electrical nerve
stimulation as an adjunct for controlling chemotherapy-induced nausea and
vomiting in gynecologic oncology patients. Cancer Nurs. 1999;22(4):307-11.
– Severity of nausea significantly lower in stimulation group on days 2-4
•
Shen J, Wenger N, Glaspy J, et al. Electroacupuncture for control of myeloablative
chemotherapy-induced emesis: A randomized controlled trial. JAMA.
2000;284(21):2755-61.*
– Stimulation vs. Sham vs. Pharmacotherapy
– Median Emesis: 5 vs. 10 vs. 15, p <0.05
– Mean Emesis: 6.29 vs. 10.73 vs. 13.41, p <0.05
•
Ozgür Tan M, Sandikçi Z, Uygur MC, et al. Combination of transcutaneous electrical
nerve stimulation and ondansetron in preventing cisplatin-induced emesis. Urol
Int. 2001;67(1):54-8.
– Active vs. Drug vs. Combination
– Nausea: 5.12 vs. 2.54 vs. 0.8, p = 0.000
– Emetic Episodes: 3.16 vs. 1.64 vs. 0.56, p <0.001
•
Roscoe JA, Morrow GR, Bushunow P, et al. Acustimulation wristbands for the relief
of chemotherapy-induced nausea. Altern Ther Health Med. 2002 ;8(4):56-7, 59-63.
– Exploratory study with no antiemetic controls in place
– Active stimulation vs. no stimulation
– Pill count: 4.1 vs. 6.6, p =0.03
*uses percutaneous stimulation with similar stimulation parameters
Summary of CINV Clinical Studies (2 of 2)
•
Roscoe JA, Morrow GR, Hickok JT, et al. The efficacy of acupressure and
acustimulation wrist bands for the relief of chemotherapy-induced nausea and
vomiting. J Pain Symptom Manage. 2003;26(2):731-42.
–
–
–
–
–
•
Treish I, Shord S, Valgus J, et al. Randomized double-blind study of the Reliefband
as an adjunct to standard antiemetics in patients receiving moderately-high to
highly emetogenic chemotherapy. Support Care Cancer. 2003;11(8):516-21.
–
–
–
–
•
Some issues with patient compliance documented, gender difference in study results
Stimulation vs. Control
Men, Vomiting: 16% vs. 50%, p <0.05
Men, Worst nausea Tx Day: 1.6 vs. 2.9, p <0.05
Men, Worst nausea overall: 2.6 vs. 4.1, p <0.05
Stimulation vs. Control
Days 1-5 Vomiting: 1.9 vs. 4.6, p =0.05
Days 1-5 Retching: 1.4 vs. 3.6, p =0.049
Days 1-5 Nausea: 1.54 vs. 3.1, p =0.018
Choo SP, Kong KH, Lim WT et al. Electroacupuncture for refractory acute emesis
caused by chemotherapy. J Altern Complement Med. 2006 Dec;12(10):963-9.*
– First Cycle (no stimulation) vs. Second Cycle (stimulation)
– Median episodes vomiting: 6 vs. 1, p <0.0001
*uses percutaneous stimulation with similar stimulation parameters
Clinical Study
Pearl ML, Fischer M, McCauley DL, et al. Transcutaneous electrical nerve stimulation as an
adjunct for controlling chemotherapy-induced nausea and vomiting in gynecologic oncology
patients. Cancer Nurs. 1999;22(4):307-11.
Patient Response
100%
90%
80%
% patients
70%
60%
50%
40%
30%
20%
10%
0%
Felt device
decreased N&V

Wished to continue
use
Would pay for
device
Found device
comfortable
Would recommend
device
Severity of nausea was significantly lower in the active device group for Days 2-4
n=42
Randomized, double-blind, parallel subjects with cross-over trial, standard antiemetic protocol
Group 1
Sham NometexTM
Group 2
Active NometexTM
Clinical study was conducted using the ReliefBand®, an earlier version of Nometex™
Clinical Study
Shen J, Wenger N, Glaspy J, et al. Electroacupuncture for control of myeloablative
chemotherapy-induced emesis: A randomized controlled trial. JAMA. 2000;284(21):2755-61.
Emetic Episodes (Days 1-5)
16
14
# episodes
12
10
8
6
*
*
4
2
0
Total Emesis Episodes (Median) p<0.001
Total Emesis Episodes (Mean) p<0.001
n=104
All breast cancer patients receiving cyclophosphamide, cisplatin,
carmustine; All receive prochlorperazine, lorazepam, diphenhydramine
hydrochloride
n=34
Standard Treatment
n=33
Sham Needling
n=37
Electro-acupuncture
* = Statistically Significant
Clinical Study
Ozgür Tan M, Sandikçi Z, Uygur MC, et al. Combination of transcutaneous electrical nerve
stimulation and ondansetron in preventing cisplatin-induced emesis. Urol Int. 2001;67(1):54-8.
Efficacy
6
Score/# episodes
5
4
3
2
*
*
1
0
Mean Nausea Scores (p = 0.000)
Mean Emetic Attacks (p = 0.000)
n=25
All patients undergoing BEP or MVEC chemotherapy
Group 1
Ondansetron (12 mg/day)
Group 2
Ondansetron + Active NometexTM
Group 3
Active NometexTM
* = Statistically Significant
Clinical study was conducted using the ReliefBand®, an earlier version of Nometex™
Clinical Study
Roscoe JA, Morrow GR, Bushunow P, et al. Acustimulation wristbands for the relief of
chemotherapy-induced nausea. Altern Ther Health Med. 2002 ;8(4):56-7, 59-63.
Nausea Severity and Antiemetic Use
7
6
Severity/# pills
5
*
4
3
2
1
0
Average Nausea (p > 0.05)
Acute Nausea (p > 0.05)
Delayed Nausea ( p < 0.06)
Antiemetic Use (p = 0.03)
n=27
All chemo patients receiving treatment on Days 1-5, 3-level crossover
Group 1
Standard care
Group 2
Sham Location Active NometexTM
Group 3
Active NometexTM
* = Statistically Significant
Clinical study was conducted using the ReliefBand®, an earlier version of Nometex™
Clinical Study
Roscoe JA, Morrow GR, Hickok JT, et al. The efficacy of acupressure and acustimulation wrist
bands for the relief of chemotherapy-induced nausea and vomiting. J Pain Symptom
Manage. 2003;26(2):731-42.
Male Patients (n=55) Vomiting
Female Patients (n=645) Nausea
5
50%
4.5
40%
4
*
*
3.5
30%
Mean score
% of patients
60%
*
20%
10%
3
2.5
2
1.5
0%
Emetic Episodes (p < 0.05)
1
0.5
4.5
Male Patients (n=55) Nausea
0
Delayed Nausea (p < 0.05)
Overall Nausea (p < 0.05)
4
Mean score
3.5
*
3
2.5
2
*
1.5
1
0.5
0
Acute Nausea (p < 0.05)
Overall Nausea (p <
0.05)
n=739
All patients with treatment regimen
containing cisplatin or doxorubicin
Group 1
Standard care
Group 2
Standard care + acupressure
Group 3
Standard care + NometexTM
* = Statistically Significant
Clinical study was conducted using the ReliefBand®, an earlier version of Nometex™
Clinical Study
Treish I, Shord S, Valgus J, et al. Randomized double-blind study of the Reliefband as an adjunct to
standard antiemetics in patients receiving moderately-high to highly emetogenic chemotherapy.
Support Care Cancer. 2003;11(8):516-21.
Efficacy (Days 1-5)
Acute CINV (Day 1)
2.5
5
4
1.5
1
*
0.5
0
# mean episodes
# mean episodes
4.5
2
3.5
3
2.5
2
1.5
*
*
*
1
Emetic episodes (p=0.25)
Nausea score (p=0.028)
0.5
0
3.5
# mean episodes
Vomiting episodes Retching episodes Severity of Nausea
(p=0.05)
(p=0.049)
(p=0.018)
Delayed CINV (Day 2-5)
Doses of
breakthrough
medications
(p=0.17)
3
2.5
n=49
All patients received moderate-highly
emetogenic chemotherapy; Antiemetics: Ondan
(8 mg), Dex (20 mg/8 mg)
n=20
Inactive NometexTM
n=24
Active NometexTM
*
2
1.5
1
0.5
*
0
Emetic episodes (p=0.032)
Nausea score (p=0.02)
* = Statistically Significant
Clinical study was conducted using the ReliefBand®, an earlier version of Nometex™
Clinical Study
Choo SP, Kong KH, Lim WT et al. Electroacupuncture for refractory acute emesis
caused by chemotherapy. J Altern Complement Med. 2006 Dec;12(10):963-9.
Acute CINV
Acute CINV
90%
8
80%
7
70%
% of patients
# of episodes
6
5
4
*
3
60%
50%
40%
30%
20%
2
*
*
10%
1
0%
0
Median Emetic Episodes (p < 0.0001)
NCI Grade 3-4 Vomiting (p NCI Grade 2-3 Nausea (p <
= 0.012)
0.0001)
n=27
All patients received Doxorubicin based chemo in combination with AC or CHOP;
All received Ondan (8 mg) + Dex (8 mg)
Cycle 1
All patients received standard antiemetic treatment
Cycle 2
All patients received electro-acupuncture in conjunction with antiemetics
* = Statistically Significant
DEVICE HISTORY
15
Overview of Device Development
Generation I (1999 – 2001)
• Technology miniaturization
• Key neuromodulation component integration
• Proprietary wave form design and
development
• 1st generation electrode design configuration
• Adjustable power/pulse levels
Moving from Prototype Model to Mass Production
Generation II (2001 – 2004)
• Pulse generator design enhancement
• Patient controllable user interface
• Further integration of wave form and pulse
design for enhanced clinical efficacy
Key Innovations to increase patient compliance and efficacy
Generation III (2004 – 2008)
• A patented electrode and lead design to
enhance pulse delivery
• Development of power regulation systems
• Enhancement of software for modulation and
waveform delivery
• Extended length device capable of being a
Single Patient Use (SPU) Device
Additional developments in a SPU unit with consistent and efficacious therapy delivery
Key Technological Features & Benefits
• Constant Current Output
– Ensure patient comfort and safety regardless of changes in skin
impedance
• Zero Net Current Waveform
– No build up of electrical energy in tissue
• Proprietary Waveform
– No short term habituation with nerve stimulation thereby
maintaining an indefinite therapeutic window
• Low Energy Output
– Achieves stimulation at 30% of the energy found in a traditional
nerve stimulator
• Advanced Power Management
– Stimulation is consistent throughout device life
Currently marketed model has incorporated key technological features
20
NMT Technology vs TENS
Low energy output
NMT-OTC
NMT-Rx
Tens Device
Output Current
and Voltage
amplitude
• Minimum 10mA
• Maximum 35mA/
110 Volts (open
circuit, no load)
• Minimum 10mA
• Maximum 40mA/
110 Volts (open
circuit, no load)
• Estimation
• Minimum 8.75mA
• Maximum 250mA
(500 ohms load)
Charge
Delivered
Per pulse
• Approximately 2.7
microcoulombs
• Maximum 3.1
microcoulombs at
+15% tolerance,
(500 ohm load)
• Approximately 3.1
microcoulombs
• Maximum 3.5
microcoulombs at
+15% tolerance,
(500 ohm load)
• Minimum 7
microcoulombs
• Maximum 75
microcoulombs
(500 ohm load)
Operating
Temperature
• 50°F to 113°F (10°C
to 45°C)
•
• 0°C to 50°C
• 31Hz
• 31Hz
• 50 to 500Hz
• 350 microseconds
• 350 microseconds
• Less than 800
microseconds
Vibration
frequency
Mechanical
shock Duration
50°F to 113°F
(10°C to 45°C)
Reference: 1.TF-01 Rev D OTC ReliefBand-signed; 2. TF-02 Rev F Rx Relief Band; 3. AAMI Standard
Transcutaneous electrical nerve stimulators
Clinical Study
35
35
30
30
25
25
# of patients
# of patients
Yong H.Kim, Kyo S, Hee J.Lee, et al. A Study on the efficacy of several neuromuscular monitoring
modes at the P6 acupuncture point in preventing postoperative nausea and vomiting
Anesth Analg 2011; 112:819-23
PONV at 6h
PONV at 24h
20
15
*
10
*
*
20
15
*
*
10
*
5
5
0
0
Nausea
(p=0.044*)
Vomiting
(p=0.002*)
n=52
Group Tetanus
N=53
Group DBS
n=53
Group TOF
n=52
Group ST
n=54
Group Control
Total PONV
(p=0.022*)
Rescue antiemetics
(p=0.084)
* = Statistically Significant between control and tetanus groups
Nausea
(p=0.001*)
Vomiting
(p=0.001*)
Total PONV
(p=0.038*)
Rescue antiemetics
(p=0.365)
Tetanus (50 mA, 50 Hz) over the median nerve
showed significant reduction in PONV when
compared to ST stimulation over the ulnar nerve.
Waveform Comparison – Kim et al 2011
Tetanus is brute force version of NMT waveform
Waveform
[shape]
Amplitude
Pulse
Width
Frequency
ST
[square]
50 mA
0.2 ms
1 Hz
TOF
[square]
50 mA
0.2 ms
1 TOF/15 s
50 mA
0.2 ms,
750 ms
interval
Double burst
every 20 s,
50 Hz
N/A
50 Hz, 5 s
every 10
mins
DB
[square]
Tetanus
[square]
NMT-Rx
[damped]
50 mA
10-40 mA,
0.31 ms
biphasic
31 Hz
Visual
MECHANISM OF
ACTION
Mechanism of Action
NMT’s device generates a proprietary
programmed pulse in the range of 1040 mA (depending on settings and
clinical need as determined by the
patient and physician).
These pulses stimulate neurons in
the median nerve pathway creating
an action potential.
The cascading action potentials are
sent via median nerve into the
brachial plexus which then enter the
cervical spinal cord and travel into
the spinothalamic tract which sends
signals to the brainstem.
The action potentials created reach
the brainstem emetic control center.
The action potentials activate various key
neurons within the brainstem emetic
(vomiting) control center and may
override or stimulate some of the gated
ion channel movements created by
emetic agonists.
Neurons within the emetic center then
create an action potential that regulates
the GI tract via the vagus nerve.
The interstitial cells of Cajal (ICC),
known as the pacemakers of the GI
tract, receive the action potentials via
the vagus nerve.
1. Silverthorn, Dee et.al. Human Physiology. San Francisco: Pearson/Benjamin Cummings, 2007. 2. Yoo SS, Teh EK, Blinder RA, et al. NeuroImage.
2004; 22: 932-940. 3. Geddes LA, Baker LE. Princ of App Biomed Instru. 1989; 732-747. 4. Schwartz RG. J of Back &Musc Rehab. 1998; 10(1):31-46.
5. Dilorenzo, J., Daniel and Joseph Bronzino. Neuroengineering. Boca Raton: CRC Press, 2008. 6. Michael, Adrian and Laura Borland.
Electrochemical Methods for Neuroscience. Boca Raton: CRC Press/Taylor & Francis, 2007.
The waveform of the action potentials
sent to the ICC now directly affect the
force and frequency of muscle
contraction in the stomach.
The now regulated stomach
contractions allow relief from nausea
and vomiting.
Basic Science – Direct Inhibition
• Dundee & Ghaly 1991,
Belfast, Ireland
40
35
Number of Patients
– 74 women undergoing
minor gynecologic surgery
– All received general
anesthetic and other
standard premedication
– Patients received 1 ml
saline or 1 ml 1% lidocaine
over the median nerve
prior to acustimulation for
5 minutes when under
general anesthesia
– The effect of nausea and
vomiting relief was
inhibited by lidocaine
injection
Emetic Sequelae (0-6 Hours Postop)
30
25
Neither
20
Nausea
15
Vomiting
10
5
0
Saline (n=37) Lidocaine (n=37)
When only comparing vomiting, Χ2 = 8.50, p = 0.0139
Basic Science – Brain Modulation
Bai et al 2010: Stimulation of the
PC6/Median Nerve compared to PC7
(distal to PC6 on median nerve) and GB37
(above the lateral malleoulus) showed:
1. Decreased Response in the
limbic/paralimbic-cerebellum and
subcortical areas
2. Modulation of:
1. Insula – visceral motor function
e.g. nausea, vomiting, gastro
disorders
Figure 3. Group results of brain activity patterns
2. Flocculonodular lobe –
under different epochs following acupuncture at
vestibulocerebellum e.g. motion
PC6, PC7, and GB37. Statistical significance was
disorders
thresholded at P < 0.005 (uncorrected) and a
3. Hypothalamus – autonomic
minimum cluster size of five voxels. Representative
regulation of visceral functions
color-coded statistical maps exhibited the distribution
3. Sustained effects beyond the
of foci with significant increases (shown in the
stimulation phase e.g. potential
spectrum from orange to yellow) and decreases
(shown in blue), relative to the respective baseline
dosing regimen as part of treatment
condition. Amy, amygdala; Hypo, hypothalamus.
Basic Science – Normalization of
Gastric Motility
• Hu, Stern, & Koch
1990, Penn State
Subjective Symptoms of Motion Sickness
& Gastric Tachyarrhythmia
– Nausea induced with
optokinetic drum
and EGG recorded
via stomach
electrodes
– 20 mA, 10 Hz,
biphasic waveform
for active stimulation
– Control was no
stimulation with
false electrodes
– Experiment 1 with
Chinese subjects
– Experiment 2 with
Caucasian and
African American
subjects
SSMS & Spectral Intensity of Gastric
Tachyarrhythmia for Three Groups
60
50
40
SSMS - Drum
Rotation
30
Baseline
20
Drum Rotation
10
0
Stimulation Sham (n=15)
No
(n=15)
Stimulation
(n=15)