Clinical Directions

Cardiovascular Clinical Development

2

Strengthen Claim Set

• Significant BP reductions alone and in combination

– General population– Black patients– HR reductions

• Low incidence of side effects• Once-daily efficacy maintained

over 24hrs.• Proposed MOA with 5 key

elements

• Significant BP reductions alone and in combination

– General population– Black patients– HR reductions– Incremental efficacy with 20 mg

– Can titrate with minimal trade off in side effects

– Efficacy in combination regardless of background therapy

– Similar blood pressure reductions to other 2nd line agents without side effects

• Low incidence of side effects• Once-daily efficacy maintained

over 24hrs.• Proposed MOA with 5 key elements

Current 2009

3

Three Part Strategy

Bystolic Hypertension Development

4

Current Phase IV Clinical StudiesStud

y Nam

e

Study Description Goal / Hypothesis Add’l Details

MD-04 IGT in HTN population

Favorable metabolic profile: NEB vs. PBO;Favorable metabolic profile: NEB vs. HCTZ;Antihypertensive efficacy/safety also assessed.

Bkrnd rx: ACEi/ARB

1° EPs: 2-hr O-GTT; DBP.2° EPs: HOMA-IR; SBP

MD-06 HTN + CADEvidence of antihypertensive efficacy/safety in hypertensive pts with CAD, NEB vs. carvedilolNOTE – head-to-head study with carvedilol

1° EP: DBP;2° EPs: SBP, Echo:

LVEF, MR, HDs; ETT

MD-08 NO MechanismLink NO mechanism, endothelial function, atherogenic lipid components, and oxidative stress measures to antihypertensive effects

FVR & FBF; fatty meal provocation; central

BPs

MD-11 Add On therapy in Stage II HTN

Efficacy when added to ACE/ARB.Demonstrate efficacy/safety in mod-severe hypertension; demonstrate large BP ↓s

1° EP: SBP2° EPs: DBP, ABPM

MD-16 Hispanic Hypertensive

Efficacy in hard-to-treat-hypertn population, based on physiologic and public health data, and ↑ obesity.Neutral metabolic profile, more important in this population

1°/ 2°: BPs. BMI is co-variate.

MD-17 Withdrawal Study

Post approval FDA commitment.Assess durability of antihypertn effects of NEB.Add’l experience with withdrawal of NEB.

After 3 mos NEB rx: continued rx vs

withdrawal to pbo

MD-19 T2 Diabetes PilotFavorable metabolic profile in hypertensive/T2DM pts of NEB vs metoprolol, & HCTZ; 6 mos DB rx.; potential label change

1° EP: HgbA1c2° EPs: HOMA-IR, DBP, SBP, plus …

5

Study of Hispanic Patients with HTN

• Objective: To evaluate the efficacy and safety of nebivolol monotherapy in Hispanic patients with stage I or stage II hypertension

• Population: 260 Hispanic hypertensive patients; stratified by BMI <30 or ≥ 30

• Design: 4 months, randomized double-blind parallel group study

• Treatment:– Nebivolol 5 mg titrated q 3 wks per BP goal (140/90) to 40 mg QD– Placebo

• Primary Endpoint: Reduction in seated diastolic BP

6

Time to Primary Endpoint

Flather MD et al. Eur Heart J. 2005;26:215-225.

SENIORS Study

P=0.039

NebivololPlacebo

Prop

orti

on H

avin

g an

Eve

nt (

%)

Time in Study (Months)0 6 12 18 24 30

50

40

30

20

10

0

(A)

7

Timelines for Label Change Studies

Inv. Mtg: MD-13

Q2 FY11

Q1 FY14

Q4 FY10

Q3 FY11

Q2 FY12

Q4 FY12

Q1 FY13

Q2 FY10

Q3 FY13

Q1 FY11

Q4 FY11

Q1 FY12

Q3 FY12

Q2 FY13

Q4 FY13

Q3FY10

Q2 FY14

Q3 FY14

Q4 FY14

HTN + PVD

HTN + COPD

HTN + T2D

MD-19 LPLV: April

2010

8

Claim Set 2010 and Beyond• Significant BP reductions alone and in combination (double

digit)– General population– Black patients– Hispanic patients– T2 Diabetics– COPD patients– PVD patients– HR reductions– Incremental efficacy with 20 mg

• Can titrate with minimal trade off in side effects– Efficacy in combination regardless of background therapy

• Similar blood pressure reductions to other 2nd line agents without side effects

• Effective in reducing morbidity and mortality of heart failure• Low incidence of side effects

– No impact on metabolic parameters (i.e. HbA1c in hypertensive patients)

– No impact on erectile dysfunction

• Once-daily efficacy maintained over 24hrs.• Proposed MOA with 5 key elements