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Oral Phosphodiesterase Type 5 (PDE5) Inhibitors1,2

Sildenafil

Currently available

Tadalafil and vardenafil

NDA submitted

Potent and selective for PDE5 isoenzyme



Mechanism of Action of PDE5 Inhibitors



Distribution of PDE Isoenzymes

PDE1 Testes, heart, olfactory cilia, CNS

PDE2 CNS, adrenal cortex

PDE3 Adipose tissue, cardiac muscle, vascular smooth muscle, liver,

platelets

PDE4 Neural and endocrine tissues1

PDE5 Vascular smooth muscle, corpus cavernosum, lung, kidney,

platelets1,2



Distribution of PDE Isoenzymes (cont)

PDE6 Retina (rods and cones)1,2

PDE7 Skeletal and cardiac muscle, lymphoid tissue1

PDE8 Testes, ovary, colon, small intestine

PDE9 Spleen, intestine, kidney, heart, brain

PDE10 Not reported1

PDE11 Penile smooth muscle, corpus cavernosum,2 testes, pituitary



Assumed Role of PDEs

PDE1 CNS modulation, vasodilation

PDE2 Uncertain

PDE3 Positive inotropism, vascular and airway dilation, platelet inhibition

PDE4 Airway dilation, CNS modulation, sperm and egg maturation

PDE5 Penile detumescence, vasoconstriction, platelet inhibition

PDE6 Phototransduction

Isoform Assumed Role

PDE5: Localization1,2

PDE5 is localized in vascular and penilesmooth muscle cells

Concentration in corpus cavernosum is higher than systemic vasculature

PDE5 is not localized in the following:

Cardiac myocytes Endothelial cells Lymphatic cells Cardiac conduction tissue



PDE5 Inhibitors: Selectivity for PDE5 vs Other PDEs

PDE Isoenzyme Sildenafil1,2 Tadalafil3 Vardenafil4

PDE1 >80 >10,000 >200

PDE2 >1000 >10,000 >14,000

PDE3 4000 >10,000 >3000

PDE4 >1000 >10,000 >5000

PDE6 9 780 >200

PDE7-10 nr >10,000 nr

nr = not reported.

1. Ballard SA, et al. J Urol. 1998;159:2164-2171. 2. Viagra prescribing information, January 2000. 3. Data on file, Lilly ICOS LLC. 4. Sorbera LA, et al. Drugs Future. 2001;26:141-144.

PDE5 Inhibitors: Pharmacokinetics

Cmax=change in maximum plasma concentration

Tmax=time to maximum plasma concentration

t1/2

=plasma half-life

nd=not determined

nr = not reported

*Median

1. Viagra prescribing information, January 2000. 2. Padma-Nathan H, Giuliano F. Urol Clin North Am. 2001;28:321-334.

3. Patterson B, et al. Poster presented at: 4th Congress (Biennial Meeting) of the European Society for Sexual and Impotence Research; September 30, 2001; Rome. 4. Data on file, Lilly ICOS LLC. 5. Klotz T, et al.

World J Urol. 2001;19:32-39. 6. Stark S, et al. Eur Urol. 2001;40:181-190. 7. Sorbera LA, et al. Drugs Future. 2001;26:141-144.

Parameter Sildenafil1,2 Tadalafil3,4 Vardenafil5-7

Bioavailability 40% nd nr

Cmax with food 29% no change nr

Tmax (h) 1* 2* <1

t1/2 (h) 3-5 17.5 ~4

PDE5 Inhibitors: Onset and Duration of Activity*

*RigiScan with visual sexual stimulation; oral dosing, empty stomach.

†Home setting; stopwatch recording.

‡Home setting; journal recording based on time frames.

nr = not reported.

1. Viagra prescribing information, January 2000. 2. Boolell M, et al. Int J Impot Res. 1996;8:47-52. 3. Padma-Nathan H.

J Urol. 2001;165(suppl):224, Abstract 923. 4. Sorbera LA, et al. Drugs Future. 2001;26:141-144.

PDE5 Inhibitor Onset (min) Duration (h)

Sildenafil1,2 30-60* 4*

Tadalafil3 30-45*;16† 24*‡

Vardenafil4 nr nr

Novel PDE5 Inhibitors: Pharmacokinetic Implications

Broader therapeutic window (>24 h)

Greater spontaneity

Bioavailability unaffected by food

More acceptable “real-life” setting

Greater selectivity



PDE5 Inhibitors Meet Important Patient Needs

Most patients prefer oral therapy1

Mechanism of action is physiologically-based

Newer agent(s) may offer an opportunity to increase spontaneity/flexibility

Consideration of partner needs and satisfaction1

Long-term improvement in quality of life1,2



Optimizing PDE5 Inhibitor Therapy

Incorrect use treatment failure

Patients should be advised that:

Sexual stimulation is needed1

A number of drug trials may be required

Sildenafil may be taken with food but onset of action may be delayed



Optimizing PDE5 Inhibitor Therapy (cont)

Incorrect use treatment failure

Testosterone augmentation should be prescribed in documented hypogonadism1

Risk factor modification may improve treatment outcomes2

Follow-up visits are essential3



Tadalafil Treatment Effect onSuccessful Intercourse: SEP Q3*†

*Did your erection last long enough to have successful intercourse?

†All randomized patients. Studies LVBN, LVCE, LVCO, and LVDJ.

Brock GB, et al. J Urol. 2002;168:1332-1336.

Tadalafil Treatment Effect on Improved Erections: GAQ*†

*Has the treatment you have been taking improved your erections?

†All randomized patients. Studies LVBN, LVCE, LVCO, and LVDJ.

Brock GB, et al. J Urol. 2002;168:1332-1336.

Tadalafil: Most Common Treatment-Related Adverse Events*

*Phase II/Ill – Adverse Events 2%.

McMahon CG. Paper presented at: 4th Congress (Biennial Meeting) of the European Society for Sexual and Impotence Research; September 30-October 3, 2001; Rome.

Adverse Event% of Patients Reporting Event

Placebo(n=758)

Tadalafil(n=1561)

Headache 4 11

Dyspepsia 1 7

Back pain 3 4

Myalgia 1 4

Nasal congestion 2 4

Flushing 1 4

Vardenafil: Tolerability*

*Phase IIb – Adverse Events 5%.

Porst H, et al. Int J Impot Res. 2001;13:192-199.

Adverse Event% of Patients Reporting Event

Placebo(n=152)

Vardenafil(n=438)

Headache 4 10

Flushing 1 11

Dyspepsia 0 3

Rhinitis 3 5

Cardiovascular Tolerancefor Sexual Activity

Exertion

(Metabolism)

Arousal

(Risk)



Resting1 1

Walking 2 mph, level1 2

Walking 3 mph, level1 3

"Sexual activity" pre-orgasm2 2-3

"Sexual activity" during orgasm2 3-4

Cycling 10 mph, level1 6-7

Walking 4.2 mph, 16%1 13

(Bruce treadmill stage 4)

Metabolic Equivalents (METs) of Selected Physical Activities

1. Fox SM 3rd, et al. Ann Clin Res. 1971;3:404-432. 2. Bohlen JG, et al. Arch Intern Med. 1984;144:1745-1748.

Pollock ML, et al. Heart Disease and Rehabilitation. Human Kinetics: Champaign, Ill. 1995:372.

Blood Pressure and Heart Rate During Sex

HR

(b

pm

)

BP

(m

m H

g)

SBP

HR

DBP

R I O 30

Sec

60

Sec

120

Sec

Phase of Intercourse

170

150

130

110

90

70

50

SBP = Systolic Blood Pressure

Man on Top

Man on Bottom

R = Rest; I = Intromission; O = Orgasm.

HR = Heart Rate

Man on Top

Man on Bottom

DBP = Diastolic Blood Pressure

Man on Top

Man on Bottom

Muller JE, et al. JAMA. 1996;275:1405-1409.

Risk of Acute MI Triggered by Sexual Activity

1663 MI survivors

858 sexually active prior to MI

27 sexually active in 2 hours prior to index MI

Relative risk of acute MI = 2x

Actual MI triggered by sexual activity: 0.9% of cases

Sexual Activity and Cardiac Risk Assessment

Adapted from DeBusk R, et al. Am J Cardiol. 2000;86:175-181.

Sexual activity deferred until

stabilization of cardiac

condition

Cardiovascular

Assessment and

Restratification

Indeterminate Risk

High

Risk

Low

Risk

Sexual

Inquiry

Initiate or resume sexual

activity or treatment for

sexual dysfunction

Clinical

Evaluation

Princeton Guidelines

Management Recommendations Based on Graded Cardiovascular Risk Assessment

Grade of Risk Management Recommendations

Low risk Primary care management

Consider all first-line therapies

Reassess at regular intervals (6-12 mo)

Indeterminate risk Specialized cardiovascular testing (eg, ETT, echo)

Restratification into high risk or low risk based on the

results of cardiovascular assessment

High risk Priority referral for specialized cardiovascular

management

Treatment for sexual dysfunction to be deferred until

cardiac condition stabilized and dependent on

specialist recommendations



ED Is VascularDiabetesDiabetes

HypertensionHypertensionOxidative stress

Endothelial cell

injury

VasoconstrictionVasoconstriction

Erectile dysfunctionErectile dysfunction

OutcomesOutcomes

DyslipidemiaDyslipidemia

TobaccoTobacco

ThrombosisThrombosis

AtherosclerosisAtherosclerosis

PrecursorsPrecursors

Why Use Patient Questionnaires?

Facilitate dialogue and diagnosis

Evaluate treatment changes

Examples of self-administered, standardized questionnaires

Sexual Health Inventory for Men (SHIM)1

International Index of Erectile Function (IIEF)2



SHIM Score Characterizes ED Severity*

22-25 Normal erectile function

17-21 Mild ED

12-16 Mild to moderate ED

8-11 Moderate ED

7 Severe ED



erectile dysfunction help

Health & Medicine

pde5 inhibitors1

pde5 isoenzyme

cardiac muscle

systemic vasculature

randomized patients

tadalafil treatment

corpus cavernosum

sexual stimulation