The Current Status of Vagus Nerve Stimulation VNS

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Objective: Discuss the long-term efficacy and safety data for the use of vagus nerve stimulation in treatment-resistant mood disorders. Disclosure: . The VNS device is manufactured by Cyberonics, Inc. Dr. Marangell has received research support, consulting fees and speaking fees from Cybero

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The Current Status of Vagus Nerve Stimulation VNS

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1. The Current Status of Vagus Nerve Stimulation (VNS) Lauren Marangell M.D. Brown Foundation Chair, Psychopharmacology of Mood Disorders Associate Professor of Psychiatry Baylor College of Medicine

2. Objective: Discuss the long-term efficacy and safety data for the use of vagus nerve stimulation in treatment-resistant mood disorders Presented to Panel, June 15, 2004 / Rush AJPresented to Panel, June 15, 2004 / Rush AJ

3. Disclosure: The VNS device is manufactured by Cyberonics, Inc. Dr. Marangell has received research support, consulting fees and speaking fees from Cyberonics. The data presented are from studies funded by Cyberonics. Presented to Panel, June 15, 2004 / Rush AJPresented to Panel, June 15, 2004 / Rush AJ

4. Off Label Use The use of VNS for depression and other psychiatric indications in the United States is currently investigational VNS Therapy is approved for medically refractory partial-onset seizures, ages 12 and up. The US FDA has stated that VNS Therapy is “approvable” for treatment-resistant mood disorders. Talk: Vagus Nerve Stimulation in Treatment-Resistant Depression Speaker: Lauren B. Marangell, M.D. Meeting: PC 2001 ISS 230 Cyberonics VNS is currently approved for epilepsy in the US, Europe, and Canada. VNS is also approved for the treatment of chronic or recurrent depression in patients that are in a treatment-resistant or treatment-intolerant major depressive episode. Talk: Vagus Nerve Stimulation in Treatment-Resistant Depression Speaker: Lauren B. Marangell, M.D. Meeting: PC 2001 ISS 230 Cyberonics VNS is currently approved for epilepsy in the US, Europe, and Canada. VNS is also approved for the treatment of chronic or recurrent depression in patients that are in a treatment-resistant or treatment-intolerant major depressive episode.

5. Vagus Nerve Stimulation (VNS) Pulse generator implanted in left chest wall area, connected to leads attached to left vagus nerve Outpatient procedure Since FDA approval for the treatment of certain types of seizures in epilepsy in July of 1997, the VNS pulse generator system has been implanted in over 10,000 patients worldwide.Since FDA approval for the treatment of certain types of seizures in epilepsy in July of 1997, the VNS pulse generator system has been implanted in over 10,000 patients worldwide.

6. VNS Therapy Programming Telemetric wand attached to a PC ON/OFF cycle is programmable Typical cycle: 30 sec ON 5 min OFF The pulse generator is typically left in the "no stimulation" mode for two weeks post surgery. This enables the patient to recover from the implant surgery and ensures healing prior to the beginning of stimulation. Once stimulation is ready to begin, a programming wand connected to a PC running the programming software is needed to communicate with the pulse generator. All parameter settings and changes are stored by the programming software for future reference if desired. The parameters which may be programmed include the output current (mA), the pulse width (micro seconds), the signal frequency (Hz), the signal ON time (seconds), the signal OFF time (minutes), and magnet activation. The stimulation occurs 24 hours per day, 7 days per week. When used for the treatment of epilepsy, and depending upon how programmed, the patient may use a magnet provided by the manufacturer to activate an additional stimulation cycle at any time. This is frequently done when the patient has an aura, or the beginning of a seizure. The cycle stimulated by magnet activation may abort or lessen the intensity of the seizure. The pulse generator is typically left in the "no stimulation" mode for two weeks post surgery. This enables the patient to recover from the implant surgery and ensures healing prior to the beginning of stimulation. Once stimulation is ready to begin, a programming wand connected to a PC running the programming software is needed to communicate with the pulse generator. All parameter settings and changes are stored by the programming software for future reference if desired. The parameters which may be programmed include the output current (mA), the pulse width (micro seconds), the signal frequency (Hz), the signal ON time (seconds), the signal OFF time (minutes), and magnet activation. The stimulation occurs 24 hours per day, 7 days per week. When used for the treatment of epilepsy, and depending upon how programmed, the patient may use a magnet provided by the manufacturer to activate an additional stimulation cycle at any time. This is frequently done when the patient has an aura, or the beginning of a seizure. The cycle stimulated by magnet activation may abort or lessen the intensity of the seizure.

7. Rationale for Investigating VNS Therapy in Depression Improved mood among patients receiving VNS Therapy for the treatment of epilepsy1,2 Anatomy and Physiology Stimulating the vagus nerve produces effects on norepinephrine and serotonin3 Brain imaging studies have shown that VNS Therapy modulates blood flow or metabolism in many areas of the brain that are implicated in neuropsychiatric disorders4 Huge unmet need

8. Pilot Study Design (D01, 4 site)

9. Pilot Study HRSD28 Response and Remission Rates Over 2 Years (LOCF) PMA-S Panel Meeting Backup Slide (June 15, 2004)PMA-S Panel Meeting Backup Slide (June 15, 2004)

10. Pivotal Study Design (D02, 21 sites) Presented to Panel, June 15, 2004Presented to Panel, June 15, 2004

11. Types of Outcome Analyses Presented to Panel, June 15, 2004Presented to Panel, June 15, 2004

12. 12 Pivotal Study Baseline Demographics PMA-S Panel Meeting Backup Slide (June 15, 2004)PMA-S Panel Meeting Backup Slide (June 15, 2004)

13. Pivotal Study Acute Results (12 Weeks) Presented to Panel, June 15, 2004Presented to Panel, June 15, 2004

14. Pivotal Study Long-Term Design Pre-Panel SlidePre-Panel Slide

15. Pivotal Study: Long-Term Response Presented to Panel, June 15, 2004Presented to Panel, June 15, 2004

16. Pivotal Study: Long-Term Remission PMA-S Panel Meeting Backup Slide (June 15, 2004)PMA-S Panel Meeting Backup Slide (June 15, 2004)

17. Pivotal Study: Long Term IDS-SR Sustained Response New Slide from PMA-S Amendment dated Sept. 23, 2004 [Quintiles] IDS-SR Quintiles Analyses using Sackeim MethodologyNew Slide from PMA-S Amendment dated Sept. 23, 2004 [Quintiles] IDS-SR Quintiles Analyses using Sackeim Methodology

18. Pivotal Study: Long Term HRSD24 Sustained Response New Slide from PMA-S Amendment dated Sept. 23, 2004 [Quintiles]New Slide from PMA-S Amendment dated Sept. 23, 2004 [Quintiles]

19. Average IDS for D-02 Patients With and Without an ARR Increase

20. D-02/D-04 Comparison Study

21. D-04: An Observational Study of Long-Term Outcomes in TRD 13 total study sites, including 12 from D-02 Similar study enrollment criteria with D-02 Similar age and sex distribution with D-02 Similar level of treatment resistance with D-02 Similar clinical characteristics Subjects received treatment as usual in the community with ratings at the site PMA-S Panel Meeting Backup Slide (June 15, 2004)PMA-S Panel Meeting Backup Slide (June 15, 2004)

22. Comparison Study Patient Populations are Comparable The D-02 and D-04 subjects appear to be essentially identical as regards observed prognostically important covariates. The use of a propensity adjustment strategy, a well-accepted approach to address potential imbalances in baseline covariates in observational data sets, was incorporated into the primary efficacy analysis and further demonstrated that differences in measured baseline covariates did not account for the superior outcome in the subjects who received adjunctive VNS Therapy.The D-02 and D-04 subjects appear to be essentially identical as regards observed prognostically important covariates. The use of a propensity adjustment strategy, a well-accepted approach to address potential imbalances in baseline covariates in observational data sets, was incorporated into the primary efficacy analysis and further demonstrated that differences in measured baseline covariates did not account for the superior outcome in the subjects who received adjunctive VNS Therapy.

23. Comparison Study Analyses Primary Efficacy Analyses Repeated measures linear regression analyses on raw IDS-SR30 scores over 12 months of stimulation Secondary Efficacy Analyses Additional IDS-SR analyses (raw scores, R, CR, %?) HRSD24 (raw score ?, R, CR, %?) HRSD6 (raw score ?, %?) CGI-I 9 subscale totals from the MOS SF-36 Medication use PMA-S Panel Meeting Backup Slide (June 15, 2004)PMA-S Panel Meeting Backup Slide (June 15, 2004)

24. Propensity Score To control for D-02 and D-04 differences in patient and disease characteristics, a propensity score was incorporated in the primary efficacy analysis Used to adjust for non-random treatment assignment Confirmed that differences were few and did not account for the difference in efficacy outcomes

25. 25 Statistical Significance Demonstrated for Primary Comparison Study Analysis Presented to Panel, June 15, 2004 (Slide title slightly modified from version presented to panel)Presented to Panel, June 15, 2004 (Slide title slightly modified from version presented to panel)

26. Comparison Study : 12-Month IDS-SR30 Response and Remission Rates

27. Secondary Analyses: Categorical Outcomes at 12 Months Presented to Panel, June 15, 2004Presented to Panel, June 15, 2004

28. Difference in Outcomes Between D-02 / D-04 Not Attributable to Baseline features because results hold with and without propensity adjustments Medication changes (D-02 had fewer than D-04) Placebo response is time-limited and does not grow over time Different slopes in D-02, D-04 after 3 months Different time-to-response curves PMA-S Panel Meeting Backup Slide (June 15, 2004)PMA-S Panel Meeting Backup Slide (June 15, 2004)

29. Comparison Study Summary Comparable, highly treatment-resistant groups at baseline Statistically significant result favoring adjunctive VNS therapy group on primary analysis (p<0.001) Statistical significance in both evaluable and ITT analyses Differences confirmed by secondary analyses using multiple outcome measures Presented to Panel, June 15, 2004Presented to Panel, June 15, 2004

30. Medical Management in Comparison Study Medication use was essentially the same between D-02 and D-04 patients D-04 patients actually had more medication changes than D-02 patients Among D-02 patients, non-responders had more medication changes than responders PMA-S Panel Meeting Backup Slide (June 15, 2004)PMA-S Panel Meeting Backup Slide (June 15, 2004)

31. D-02 Responders Had Significantly Fewer Antidepressant Medication Changes

32. Concomitant Mood Disorder Treatments Taken During the Study PMA-S Panel Meeting Backup Slide (June 15, 2004)PMA-S Panel Meeting Backup Slide (June 15, 2004)

33. Long-Term Safety Profile Improvement Minimal new side effects after 3 months Majority of side effects mild or moderate in severity initially Decreased incidence over time Accommodation PMA-S Panel Meeting Backup Slide (June 15, 2004)PMA-S Panel Meeting Backup Slide (June 15, 2004)

34. Side Effects Typically Diminish Over Time Presented to Panel, June 15, 2004Presented to Panel, June 15, 2004

35. 35 Safety

36. Depression Studies Safety Overview Side effects are mainly stimulation-related and typically decrease over time Low rate of treatment-related discontinuation No signal for treatment-related emergence of suicidal ideation/behavior Emergent mania/hypomania within range expected for effective antidepressant Overall, VNS therapy was well-tolerated and safe Presented to Panel, June 15, 2004Presented to Panel, June 15, 2004

37. 37 Conclusions Improvements observed with adjunctive VNS therapy are largely sustained during long-term treatment VNS therapy is well-tolerated and safe in depression clinical trials and clinical use in epilepsy VNS therapy has additional device-related benefits vs standard-of-care treatments Presented to Panel, June 15, 2002Presented to Panel, June 15, 2002

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