TRDFullPPT17E2

An introduction to VNS THERAPY in depression

TRDFullPPT17E2

TRDFullPPT17E2

The Reality of Difficult to Treat Depression

High healthcare burden (1)

Increased suicide risk (3)

High health care utilisation (4)

Resistant depression accounts for 40% of annual depression treatment costs (2)

Current antidepressant therapies have limited effectiveness for patients with true resistant depression (3)

High Healthcare

burden

Current Therapy Limited

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TRDFullPPT17E2

Relapse during psychopharmaceutical

therapy (1)

57%

Relapse after remission with ECT

within 6 months (2)

65%

Challenges of Difficult to Treat Depression

3

TRDFullPPT17E2

Treatment of Difficult to Treat Depression

Reduce relapse and recurrence

Restore psychosocial function

Reduce risk of suicide

Optimise safety and side-effects

Optimise compliance

Improve Quality of Life(2)

Aim for long-term disease management

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TRDFullPPT17E2

What is VNS Therapy?

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TRDFullPPT17E2 Antidepressant Mechanisms of VNS Summary

Short- and medium-term antidepressant effects of VNS

Long-term antidepressant effects of VNS

Attenuates interhemispheric imbalance associated with depression (right side inhibition & left side activation) (3)

Emerging antidepressant effects of VNS

Increases availability of serotonin and noradrenalin (1,2)

May reduce inflammation contributing to depression (4)

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TRDFullPPT17E2 D-23 VNS Registry – US (2006 – 2015)

History and Study Design

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Objective Follow clinical course and outcome for TRD patients treated with and without adjunctive VNS Therapy (requirement of FDA for approval)

Observational study of unipolar or bipolar depression.

500 VNS + TAU ‘v’ 300 TAU

Treated at same medical centres

Patient Choice

5 Years

D-21

Subjects permitted to choose between VNS and TAU at screening

Pts from completed D-21 dose finding study could enter TRD registry

All received VNS and entered the VNS Group

TRDFullPPT17E2 D-23 VNS Registry - US Patient Demographics – Safety Population

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Characteristic VNS Therapy + TAU D23 + D21 TAU

Patient Number 494 301

Female % 70.9 70.1

% Caucasian 96.8 91.0

Mean Age at BL (yrs) (SD) 48.9 (10.1) 49.9 (11.1)

Mean Age at onset of Depression (SD) 20.9 (11.8) 21.1 (11.4)

Mean Age at dx of Depression (SD) 28.9 (10.8) 29.5 (11.9)

# MDE’s (mean, SD) 14.9 (24.1) 12.0 (23.9)

# Failed treatments (mean, SD)1 8.2 (3.30) 7.3 (2.92)

#Suicide attempts (mean, SD) 1.8 (4.0) 1.2 (2.4)

Prior ECT (%) 57% 40%

Psychiatric hospitalisations within 5 years prior to enrollment 3.0 (4.6) 1.9 (4.7)

Baseline MADRS Score 33.1 (7.0) 29.4 (6.9)

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TRDFullPPT17E2 D-23 VNS Registry - US Patient Demographics

Diagnosis VNS Therapy + TAU D23 + D21 TAU

Recurrent MDD (moderate) 12.8% 22.9%

Recurretn MDD (severe) 45.5% 31.6%

Single MDD (moderate) 3.2% 10.0%

Single MDD (Severe) 11.3% 12.0%

Bipolar I Depressed (Moderate) 5.1% 7.0%

Bipolar I Depressed (Severe) 12.6% 4.0%

Bipolar II Depressed 9.5% 12.6%

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TRDFullPPT17E2 C

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Cumulative First-Time Responders by Visit Month by Treatment Group: MADRS – VNS + TAU vs TAU (ITT Population)

0

10

20

30

40

50

3 mo 6 mo 9 mo 12 mo 18 mo 24 mo 30 mo 36 mo 42 mo 48 mo 54 mo 60 mo

20.3 22.3

8

31.8 34.4 16

38.8 42.8 20.7

45.2 50.4 25

49.4 53.3 27.2

53.9 56.8 29

56.9 59.5 31.9

61.4 63.6 33.3

61.7 64.4 35.1

63.2 66.2 37.3

63.8 67.2 38.7

63.8 67.8 40.9

Follow-up Visit Month

VNS D23 VNS D23+D21

TAU

Database lock as of 5 May, 2015

Cyberonics Inc.

Protocol: D23/TRD Registry

VNS + TAU

TAU

D-23 VNS Registry - US MADRS Response

Cumulative Response Rate at 5 years

Primary Endpoint – First Time Response Rate based on MADRS

67.6% for VNS Therapy vs. 40.9% for TAU (P<0.001)

60

70

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TRDFullPPT17E2

Cumulative First-Time Remitters by Visit Month by Treatment Group: MADRS – VNS + TAU vs TAU (ITT Population)

0

10

20

30

40

50

3 mo 6 mo 9 mo 12 mo 18 mo 24 mo 30 mo 36 mo 42 mo 48 mo 54 mo 60 mo

7.3 8

2.5

14.3 15.8 6.5

18.2 20.7 9.4

22.1 26

12.7

25.1 28

14.5

28.7 30.5 16.3

31.7 33.6 18.1

34.4 36.7 19.9

36.5 38.7 21.3

37.7 40.9 22

38.9 41.9 22.7

40.7 43.3 25.6

VNS D23 VNS D23+D21

TAU

Database lock as of 5 May, 2015

Cyberonics Inc.

Protocol: D23/TRD Registry

VNS + TAU

TAU

D-23 VNS Registry - US MADRS Remission

Cumulative Remission Rate at 5 years

43.3% for VNS Therapy D-23 + D-21 vs. 25.7% for TAU (P<0.001)

Secondary Endpoint – First Time Remission Rate based on MADRS (≤9)

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Follow-up Visit Month

TRDFullPPT17E2 C

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Cumulative First-Time Response by Visit Month by Treatment Group: MADRS – VNS D-23 + D-21 vs. TAU (ITT Population) based on whether

subjects had responded or not to ECT

0

10

20

30

50

70

3 mo 6 mo 9 mo 12 mo 18 mo 24 mo 30 mo 36 mo 42 mo 48 mo 54 mo 60 mo

15.4 4.5 23.8 15.6

24.6 13.6 35.4 23.9

27.7 18.1 43.1 31.2

35.4 24.9 49.7 37.6

35.4 29.4 51.9 42.2

40 29.4 55.8 46.8

43.1 29.4 59.7 50.5

47.7 29.4 66.3 55.1

49.2 31.7 68

59.7

49.2 34

69.1 59.7

53.8 34

70.2 59.7

56.9 34

71.3 59.7

Follow-up Visit Month

TAU ECT Resp TAU ECT No resp

VNS ECT Resp VNS ECT No Resp

VNS ECT Resp

VNS ECT No Resp

TAU ECT No Resp

D-23 VNS Registry - US MADRS – Response by History of Prior Response to ECT

Cumulative Response Rate Based on ECT Response (yes/no)

Exploratory Analysis – Response based on MADRS

VNS (ECT resp) (n=129) 71.3%

TAU (ECT resp) (n=37) 56.9%

VNS (ECT nonresp) (n=65) 59.7%

TAU (ECT nonresp) (n=15) 34.0%

TAU ECT Resp

40

60

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TRDFullPPT17E2

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VNS for Depression in England – Current Spread of Centres

TRDFullPPT17E2

Conclusions

VNS Therapy® is an effective treatment for Difficult to Treat Depression

There is a significant cumulative and sustained effect of treat-ment over time

VNS Therapy has a favorable safety profile

Risk of suicide is decreased by adding VNS Therapy

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There is evidence of improved QOL and restored psychosocial functioning

Compliance is guaranteed

With limited treatment options and the morbidity/mortality associated with the disease, VNS Therapy® is needed in a psychiatrists’ therapeutic armamentarium to treat and manage these difficult to treat patients