glaucoma slides

Overview of Glaucoma• Heterogeneous group of disorders• Affects more than 67 million people• Second leading cause of blindness worldwide;

leading cause in blacks• Permanent loss of vision due to death of retinal

ganglion cells and their axons• Treatment aimed at slowing or stopping progression

of damage

Risk Factors for Glaucoma•Elevated intraocular pressure (IOP)•Diurnal fluctuation in IOP•Patient characteristics

– Cup/disc– Advanced age– Race (Blacks 6-8 X Non-Blacks)– Family history– Concomitant conditions (e.g., diabetes, BP) – Myopia

•Compromised ocular hemodynamics

Normal Drainage of Aqueous Humor

Elevated IOP:A Major Risk Factor for Visual Field Damage

• Blockage of the eyes’ natural drainage system increases IOP

• IOP exceeding 21 mmHg falls above the normal range

• Goal of therapy is reducing IOP and preserving visual field

Major Types of Glaucoma• Open-angle glaucoma• Angle-closure glaucoma• Normal (low) tension glaucoma• Juvenile glaucoma• Congenital glaucoma• Secondary glaucomas

Glaucoma Treatment Options• Medications

– Beta-adrenergic blockers– Miotics (cholinergics)– Sympathomimetics– Hyperosmotic agents– Carbonic anhydrase inhibitors– Selective alpha2-adrenergic agonists– Prostaglandin analogues

• Laser surgery– Trabeculoplasty– Iridotomy

• Incision surgery

Mean IOP and Visual Field Loss•Advanced Glaucoma Intervention Study (AGIS) 7

– 586 eyes followed over 6 or more years– Positive correlation between IOP and visual field

loss– Patients who were below 18 mm Hg at 100% of

visits had little or no progression over 6 years– Patients with 25% of visits >18 mm Hg had

greater risk of clinically significant visual field progression over 6 years.

VanVedlhuisen, et al, AJO 130, 429-440 October 2000

Follow-up (years)

5

4

3

2

1

0-1

0 1 2 3 4 5 7 86

100% of visits75 - 99% of visits50 - 74% of visits0 - 49% of visits

Mea

n ch

ange

in v

isua

l def

ect s

coreAGIS 7

Sustained IOP reduction below 18 mmHg is correlated with stability of visual field

Percent of Visits with IOP Less Than 18 mmHg

AGIS Investigators, 2000, Am. J. Ophthalmol., 130, 429-440

Follow-up (years)

5

4

3

2

1

0-1

0 1 2 3 4 5 7 86

100% of visits75 - 99% of visits50 - 74% of visits0 - 49% of visits

Mea

n ch

ange

in v

isua

l def

ect s

coreAGIS 7

Sustained IOP reduction below 18 mmHg is correlated with stability of visual field

Percent of Visits with IOP Less Than 18 mmHg

AGIS Investigators, 2000, Am. J. Ophthalmol., 130, 429-440

MEAN IOP20.2 mmHg

16.9 mmHg14.7 mmHg

12.3 mmHg

Diurnal IOP Fluctuation and Visual Field Loss

• ASRANI, et. al. 2000, Large Diurnal Fluctuations in Intraocular Pressure Are an Independent Risk Factor in Patients With Glaucoma, J. Glaucoma, 9, 134-142– Diurnal IOP fluctuation positively correlated with visual

field loss– Patients used multiple home tonometry assessments,

compared to office visit readings

Asrani et al: Methodology

• 64 patients (105 eyes)• Home tonometry by the patient 5X daily for 5 days• Self-tonometer (CDSTechnology, L.L.C.)• Visual field progression of patients tracked over 8

years

Asrani, et al., 2000, Large Diurnal Fluctuations in Intraocular Pressure Are an Independent Risk Factor in Patients With Glaucoma, J. Glaucoma, 9, 134-142

Asrani et al: Home Tonometry

• Range of Home IOPThe difference between the highest and lowest home tonometry readings over the entire 5 day period


Asrani et al: Home TonometryAll patients

Parameter Mean ±SD(mm Hg) Range (mm Hg)

Range of homeIOP over days

(total fluctuation)10.0 ± 2.8 4.4 –18.5



Asrani et al: Diurnal IOP Fluctuation Correlated With Visual Field Progression

Lowest range of home IOP (Lowest 25th percentile)

43% - No further visual field loss

12% - No further visual field loss

Highest range of home IOP (Highest 25th percentile)

Summary - Important Goals of Therapy

• Reduction in mean IOP to <18 mm• Control of diurnal IOP fluctuation

throughout the day

Prostaglandin AnaloguesHelping To Achieve Goals of Therapy

• Achieved new “gold standard” beyond beta blockers for total IOP reductions

• Once per day dosing (i.e. sustained diurnal activity)

Prostaglandin AnaloguesU.S. Launches

• latanoprost (Pharmacia) -- August 1996• unoprostone (Novartis) -- September 2000• bimatoprost (Allergan) -- March 2001• travoprost (Alcon) -- March 2001

Prostaglandin Analogues:Mechanism of Action

• Pro-drugs, requiring hydrolysis by corneal enzymes before becoming the active “free acids”

• Free acids bind to FP receptors in the ciliary body• Activation of FP receptors up-regulates matrix metalloproteinases

(MMPs) which degrade extracellular proteins (i.e collagen) in the uveoscleral pathway

• Results in an increase in uveo-scleral outflow and a lowering of intraocular pressure

• Prostaglandin analogues may also enhance outflow through the trabecular meshwork

Prostaglandin-F2 (PGF2) • Naturally occurring- derived from fatty acid• Potent FP receptor agonist• Lowers IOP by increasing aqueous humor outflow through

the uveoscleral pathway and trabecular pathways• Causes side effects due to nonselectivity

Chemical Structure of PGF2 Isopropyl Ester

POTENCY AND SELECTIVITY

ESTER PRODRUG, PENETRATION

OH

OH

O H

O O

Chemical Structure of Prostaglandin Analoguesand PGF2 Isopropyl Ester

Latanoprost

Isopropyl Unoprostone

PGF2 isopropyl ester

OH

OH

OH

O NH

Bimatoprost

CF3OH

OH

OOH

O O

Travoprost

OH

OH

OH

O O

OH

OH

O

O O

OH

OH

OH

O O


Latanoprost



OH

OH

OH

O NH

Bimatoprost

CF3OH

OH

OOH

O O

Travoprost

OH

OH

OH

O O

OH

OH

O

O O

OH

OH

OH

O O


Latanoprost



OH

OH

OH

O NH

Bimatoprost

CF3OH

OH

OOH

O O

Travoprost

OH

OH

OH

O O

OH

OH

O

O O

OH

OH

OH

O O


Latanoprost



OH

OH

OH

O NH

Bimatoprost

CF3OH

OH

OOH

O O

Travoprost

OH

OH

OH

O O

OH

OH

O

O O

OH

OH

OH

O O

Activity of PGF2 Isopropyl Ester Prodrug• Hydrolyzed to PGF2 (acid) in the cornea• Activates FP receptors on ciliary muscle• Stimulates matrix metalloproteinase production,

opening the uveoscleral pathway• 10 to 100 more potent than PGF2 in

lowering IOP• Side effects remain an issue due to

nonselectivity

Bimatoprost is a Prodrug(17-phenyl trinor prostaglandin F2ethyl amide)

“There is some controversy as to whether 17-phenyl trinor PFG2 ethyl amide is a prodrug analogous to prostaglandin ester prodrugs such as latanoprost.

...Investigations in our lab have shown that bimatoprost is converted by an amidase enzymatic activity in the bovine and human cornea to yield the corresponding free acid, with a conversion rate of about 40 g/g corneal tissue/24 hours. The free acid, 17-phenyl trinor PFG2, is a potent FP receptor agonist. In human and animal models of glaucoma, FP receptor agonist activity corresponds very closely with intraocular hypotensive activity.”

Reference: Cayman Chemical Websitehttp://www.caymanchem.com/cgi-bin/product?catalog_num=16820

Bimatoprost is a Prodrug(17-phenyl trinor prostaglandin F2ethyl amide)

Reference: Cayman Chemical Websitehttp://www.caymanchem.com/cgi-bin/product?catalog_num=16821

“Although it has been claimed that prostaglandin amides are not converted to the free acids in vivo, studies in our laboratories have shown that bovine and human corneal tissue converts the amides of various prostaglandins to the free acids with a conversion efficiency of about 10-20% relative to the hydrolysis of isopropyl esters. 17-phenyl trinor PGF2a amide would be expected to show the typical intraocular effects of latanoprost, but with the much slower hydrolysis pharmacokinetics of the prostaglandin N-amides”

Bimatoprost is an FP Agonist Prodrug

NA Sharif, et al., 2001, Bimatoprost and its Free Acid are Prostaglandin FP Receptor Agonists, Eur. J. Pharmacol., 432, 211-213

Maxey, K.M., Johnson, J., Camras, C.B., et al., 2001 The hydrolysis of bimatoprost in corneal tissue generates a potentprostanoid FP receptor agonist, [In Press] Survey of Ophthalmology

K.M. Maxey, K.M., Johnson, J., Camras, C.B., and LaBrecque, J., The hydrolysis of bimatoprost in corneal tissue generates a potent prostanoid FP receptor agonist, Proceedings of the American Glaucoma Society 12th Annual Meeting, February 28-March 3, 2002

Time (hours)0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

0

10

20

30

40

50

Below the Limit of Quantitation

Con

cent

ratio

n (n

g/m

L)

Bimatoprost (Acid)Bimatoprost

Bimatoprost and Bimatoprost (Acid) in Aqueous Humor of Dutch Belted Rabbits

Single Topical Ocular Instillation of 0.03% Bimatoprost Solution

30

Travoprost:Preclinical Data

Binding Affinity of FP Agonists at Prostaglandin Receptors

Note: Lower number implies higher affinity

Adapted from MR Hellberg, et al. 2001, J. Ocular Pharmacol. Therapeu, 17 (5) 421-432 and NA Sharif,et. al., 2001, Eur. J. Pharmacol., 432, 211-213

Receptor Binding Affinity(Ki, nM)Compound

FP EP1

PGF2 129 ± 12

IOPVasodilation

EP1 Receptors & Pain Perception

“Prostaglandins act both at peripheral sensory neurons and at central sites … to evoke hyperalgesia. Recent data support involvement of … EP1 receptors in pain.” 1,2,3

Science, 30 Nov 2001, Vol 294, p.1874

1 S. Narumiya, G.A. FitzGerald, J. Clin. Invest. 108, 25 (2001)2 S.L. Tilley et al., J. Clin. Invest. 108, 25 (2001)3 Y. Sugimoto et al., Prog. Lipid Res. 39, 289 (2000)

EP1 Receptors & Inflammation“Our results suggest that PGE(2) may profoundly alter the nature of the mast cell degranulation and cytokine responses at sites of allergic inflammation through an EP(1)/EP(3)-dependent mechanism.”1

1Gomi K, Zhu FG, Marshall JS. 2000, Prostaglandin E2 selectively enhances the IgE-mediated production of IL-6 and granulocyte-macrophage colony-stimulating factor by mast cells through anEP1/EP3-dependent mechanism. J Immunol 165(11):6545- 52

Departments of Microbiology and Immunology, and Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.

EP1 Receptors & Pruritus“Further studies involving selective agonists and antagonists suggested that EP1 receptors, IP receptors and PGD2-sensitive receptors may mediate prostanoid-induced conjunctival itching”1 .

1Woodward DF, Nieves AL, Friedlaender MH., 1996, Characterization of receptor subtypes involved in prostanoid-induced conjunctival pruritus and their role in mediating allergic conjunctival itching. J Pharmacol Exp Ther 279(1):137-42

Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.



Inflammation,Pain

Pruritus


FP EP1

PGF2 129 ± 12 600




FP EP1

PGF2 129 ± 12 600

Unoprostone (acid) 5,649 ± 893 12,000





FP EP1

Latanoprost (acid) 92 ± 14 2000

PGF2 129 ± 12 600







FP EP1

Bimatoprost (acid) 83 ± 2 95


PGF2 129 ± 12 600






FP EP1



PGF2 129 ± 12 600





FP EP1

Travoprost (acid) 52 ± 2 9,540



PGF2 129 ± 12 600






FP EP1

Travoprost (acid) 52 ± 2 9,540



PGF2 129 ± 12 600




Binding Affinity of FP Agonists at PG Receptors

Receptor Binding Affinity (Ki ,nM)Compound FP DP EP1 EP3 EP4 IP TPTravoprost

(acid) 52 ± 2 46,000 9,540 3,500 41,000 >90,000 >120,000

PGF2 129 ± 12 18,000 600 24 400 500,000 200,000

Latanoprost(acid) 92 ± 14 26,000 2,000 7,900 75,000 >90,000 >60,000

Unoprostone(acid) 5649 ± 893 >43,000 12,000 15,200 22,000 >30,000 >30,000

Bimatoprost(acid) 83 ± 2 >90,000 95 1,270 26,000 >100,000 >100,000

Adapted fromMR Hellberg, et. al. 2001, J. Ocular Pharmacol. Therapeu, 17 (5) 421-432NA Sharif,et.. al., 2001, Eur. J. Pharmacol., 432, 211-213BW Griffin et. al., 1997, J. Pharmacol. Exp. Ther., 281(2), 845-854NA Sharif, et. al., 2000, J. Pharmacol. Exp. Ther., 293, 321-328NA Sharif, et. al., 1999, J. Pharm Pharmacol.., 51, 685-694

Functional Activity of Travoprost andOther FP Agonists

0

20

40

60

80

100

120

10-11 10-10 10-9 10-8 10-7 10-6 10-5 10-4 10-3

Higher Potency Molar Concentration

Full Agonist, Emax =100%

GreaterEfficacy

PI Tu

rnov

er R

espo

nse

(% C

ontro

l)

Adapted fromMR Hellberg, et. al. 2001, J. Ocular Pharmacol. Therapeu, 17 (5) 421-432; NA Sharif,et.. al., 2001, Eur. J. Pharmacol., 432, 211-213; BW Griffin et. al., 1997, J. Pharmacol. Exp. Ther., 281(2), 845-854

Unoprostone acid

Latanoprost acid

Travoprost acid

Pharmacology References• MR Hellberg, et al. 2001, Preclinical Efficacy of Travoprost, a Potent and

Selective FP Prostaglandin Receptor Agonist, J. Ocular Pharmacol. Ther., 17, 421-432

• NA Sharif, et al., 2001, Bimatoprost and its Free Acid are Prostaglandin FP Receptor Agonists, Eur. J. Pharmacol., 432, 211-213

• NA Sharif, et al., 1999, [3H]AL-5848 ([3H]9-(+)-Fluporstenol). Carboxylic Acid of Travoprost (AL-6221), a Novel FP Prostaglandin to Study the Pharmacology and Autoradiographic Localization of the FP Receptor, J. Pharm. Pharmacol., 51, 685-694

• BW Griffin, et al., 1997, FP Prostaglandin Receptors Mediating Inositol Phosphate Generation and Calcium Mobilization in Swiss 3T3 Cells: A Pharmacological Study, J. Pharmacol. Exp. Ther., 281, 845-854

-6 0 6 12 18

BP HR pCO2 pO2 ONH FLOW

% Change

Vehicle

Travoprost

Effect of Topical Travoprost on Rabbit Optic Nerve Head Blood Flow (Laser Doppler Flowmetry)†

*

* P < 0.05 vs baseline and vehicle†Rabbits do not respond to PG analogues for IOP change

46

Travoprost:Clinical Data

Travoprost Clinical Studies: Summary

Dose responseAMPM

28 days 28 days

138227

5 9

PlaceboPlacebo

Study Duration No. Patients No. Sites Comparators

Pivotal efficacy United StatesUnited StatesInternational

12 months 6 months 9 months

6 monthsAdjunctive therapy

United States 427 46

Timolol + placebo

Latanoprost,TimololTimololTimolol

444464

801605573

Dose-response Studies (AM vs. PM)

Study C-97-02(PM dosing)

Study C-96-52(AM dosing)

Travoprost Concentration (%)0 0.001 0.002 0.003 0.004 0.005 0.006

Mea

n IO

P Ch

ange

(mm

Hg)

-8

-7

-6

-5

-4

-3

-2

-1

0

From Garadi, R., et. al., Invest. Ophthalmol. Vis Sci., 1999, 40 (4) Abst 4378

• Across all studies, mean IOP reductions were up to:– 9 mmHg– 33 %

• In U.S. 12-month pivotal study, mean IOP reductions were:

– from 6.6 to 8.1 mmHg– up to 1.8 mmHg greater in black than non-black patients

Key Clinical Trial Efficacy Results

• In U.S. 12-month pivotal study, mean IOP reductions were:

– from 6.6 to 8.1 mmHg• In International 9 month pivotal study, mean IOP

reductions were up to:– 9 mmHg– 33 %

Key Clinical Trial Efficacy Results

US 12-month Pivotal Study Design• Prospective, double-masked, parallel, randomized• Qualifying baseline IOP

– 24 to 36 mmHg at 8 AM– 21 to 36 mmHg at 10 AM and 4 PM

• Travoprost 0.004% q.d. or latanoprost 0.005% q.d. administered at 8 PM in each eye. Timolol 0.5% b.i.d. administered at 8 AM and 8 PM

• IOP measurements at 8 AM, 10 AM, and 4 PM• Clinical assessments at 0.5, 1.5, 3, 4.5, 6, 9, and 12

months

Travoprost DemographicsUS 12-month pivotal study

Iris Color

HAZELGREENBLUEGREY

RaceCAUCASIAN

ASIANOTHER

Travoprost 0.004%

N P value0.807

138

28

1* 0.395

2310525

Timolol0.5%

N

146

--9

2811597

Latanoprost0.005%

N

135BLACK 49 24.9 40 20.543 22.3

213

-- --BROWN 106 53.8 90 46.2114 59.1

248

389

%

70 .1

1.04.1

0.5

11.75.1

26.42.5

%

74.9

--4.6

--

14.45.6

30.33.6

%

69.9

1.06.7

12.44.1

19.74.7

--

*Iris color not obtained for one patient.

Travoprost DemographicsUS 12-month pivotal study

Iris Color

HAZELGREENBLUEGREY

RaceCAUCASIAN

ASIANOTHER

Travoprost 0.004%

N P value0.807

138

28

1* 0.395

2310525

Timolol0.5%

N

146

--9

2811597

Latanoprost0.005%

N

135BLACK 49 24.9 40 20.543 22.3

213

-- --BROWN 106 53.8 90 46.2114 59.1

248

389

%

70 .1

1.04.1

0.5

11.75.1

26.42.5

%

74.9

--4.6

--

14.45.6

30.33.6

%

69.9

1.06.7

12.44.1

19.74.7

--

*Iris color not obtained for one patient.

Mean IOP at Baseline:US 12-Month Pivotal Study

15

20

25

30

Time

Mea

n IO

P (m

mHg

)

Travoprost (n = 197)

Latanoprost(n = 195)

Timolol(n = 193)

8 AM 10 AM 4 PM

No difference between groups, p=0.1017Adapted from Netland, P.A., et. al, American Journal of Ophthalmology, 2001, 132:472-484

Powerful Reduction in Mean IOPMean IOP at 10 AM*, U.S. 12-month pivotal study

Study Visit (Months)

(n=197)Travoprost 0.004%

Adapted from Netland, P.A., et. al, American Journal of Ophthalmology, 2001, 132:472-484

1617181920212223242526

0 0.5 1.5 3 4.5 6 9 12

Mea

n IO

P (m

mHg

)

*14 hours post dose

Travoprost vs LatanoprostMean IOP, pooled visits U.S. 12-month pivotal study

15

17

19

*p<0.02

*

8 AM 4 PM10 AM

Time

Mea

n IO

P (m

mHg

)

Travoprost 0.004%(n=197)

Latanoprost 0.005%(n=193)

Adapted from Netland, P.A., et. al, American Journal of Ophthalmology, 2001, In PressAdapted from Netland, P.A., et. al, American Journal of Ophthalmology, 2001, 132:472-484

*p<0.02

16

17

18

19

20

0.5 3 6 12Months

Mea

n IO

P (m

m H

g)

*

Travoprost 0.004% Latanoprost 0.005%

Travoprost vs LatanoprostMean IOP at 4 PM†, U.S. 12-month pivotal study


†20 hours post dose*p=0.0012

Travoprost vs. Timolol:Mean IOP at 10 AM†, U.S. 12-month pivotal study

1617181920212223242526

0 0.5 1.5 3 4.5 6 9 12

†14 hours post Travoprost, 2 hours post timolol*p<0.0007

Mea

n IO

P (m

mHg

)

Study Visits (Months)

* * * * * **

Travoprost(n=197)

Timolol(n=195)


Travoprost Superior to Timolol Throughout the DayMean IOP, pooled visits, U.S. 12-month pivotal study

1.2 mmHg D 1.6 mmHg D 1.7 mmHg D

19

21

17

Travoprost(n = 197) (n = 195)

Timolol

8 AM 10 AM 4 PM

Mea

n IO

P (m

mHg

)

Time *p<0.0001

15

**

*


TRAVATAN (travoprost ophthalmic solution) 0.004% Sterile

Clinical StudiesIn clinical studies, patients with open-angle glaucoma or ocular hypertensionand baseline pressure of 25-27 mmHgwho were treated with TRAVATAN Ophthalmic Solution 0.004% dosedonce-daily in the evening demonstrated7-8 mmHg reductions in intraocular pressure. In subgroup analyses of thesestudies, mean IOP reduction in blackpatients was up to 1.8 mmHg greaterthan in non-black patients. It is notknown at this time whether this differenceis attributed to race or to heavilypigmented irides.

In a multi-center, randomized, controlled trial, patients with mean baseline intaocular pressure of 24-26 mmHg on TIMOPTIC 0.5% BID who were treated with TRAVATAN 0.004% dosed QD adjunctively to TIMOPTIC* 0.5% BID demonstrated 6-7 mmHg reductions inintraocular pressure.

XALATAN* (latanoprost ophthalmic solution 0.005%)

50 g/mL

Clinical StudiesPatients with mean baseline intraocularpressure of 24-25 mmHg who were treatedfor 6 months in multicenter, randomized,controlled trials demonstrated 6-8 mmHgreductions in intraocular pressure. ThisIOP reduction with XALATAN* SterileOphthalmic Solution 0.005% dosedonce daily was equivalent to the effectof Timolol 0.5% dosed twice daily.

LUMIGAN*

(bimatoprost ophthalmic solution) 0.03%

Clinical StudiesIn clinical studies of patients with openangle glaucoma or ocular hypertensionwith a mean baseline IOP of 26 mmHg,the IOP-lowering effect of LUMIGAN*

(bimatoprost ophthalmic solution)0.03% once daily (in the evening)was 7-8 mmHg.

*Trademarks are the property of their respective owners.*Trademarks are the property of their respective owners.

• Since July 1988, FDA has required pharmaceutical companies to evaluate all critical variables in the NDA which include age, gender, race, and other relevant factors.

Subgroup Analyses

• The subgroup analyses were prospectively planned prior to study initiation, as required by the FDA

• Patients were qualified and randomly assigned to treatment groups in the TRAVATAN® clinical trials

• Clinically relevant and statistically greater IOP lowering benefits were observed in black patients. These analyses were subjected to rigorous evaluation by the FDA, which resulted in their inclusion in the TRAVATAN® package insert

• Only TRAVATAN® has demonstrated greater IOP reduction in black patients

Subgroup Analyses

Travoprost Efficacy in Black PatientsMean IOP in black patients, pooled visits, U.S. 12-month pivotal study

8 AM 10 AM 4 PM

Time

Mea

n IO

P (m

mHg

)

15

17

19

21

23

Timolol (n=40)Latanoprost (n=43)Travoprost (n=49)

p=0.0001 Travoprost vs Timololp<0.036 Travoprost vs Latanoprost


16

17

18

19

20

8AM 10AM 4PM

Time

Mea

n IO

P (m

mHg

)

*

** ***

*p=0.0354**p=0.0143

***p=0.0356


Latanoprost 0.005%(n=43)


Travoprost vs. Latanoprost in Black PatientsMean IOP in black patients, pooled visits,

U.S. 12-month pivotal study

15

17

19

21

23

25

27

0 0.5 1.5 3 4.5 6 9 12Months

Mea

n IO

P (m

mH

g)

Travoprost 0.004% Latanoprost 0.005% Timolol 0.5%

Travoprost vs. Latanoprost and Timolol in Black PatientsMean IOP at 10 AM, U.S. 12-month pivotal study

*‡ *‡ * * * * *‡

* p 0.0007 Travoprost vs Timolol‡ p< 0.034 Travoprost vs LatanoprostAdapted from Netland, P.A., et. al, American Journal of Ophthalmology, 2001, 132:472-484

15

17

19

21

23

25

27

Baseline 1.5 3 6 12

Months

Mean

IOP

(mm

Hg)

4.4

mmHg

* * * *

*p<0.0002


Timolol 0.5%(n=40)

Travoprost vs. Timolol in Black PatientsMean IOP in black patients at 4 PM, U.S. 12-month pivotal study


20

30

40

50

60

70

80

90

100

< 22 mmHg < 20 mmHg < 18 mmHg

% P

atie

nts

Resp

ondi

ng a

t 4 P

M

Travoprost 0.004%(n = 49)

Latanoprost 0.005%(n = 43)

Timolol 0.5%(n = 40)

86

75

96

86

74

5865

47

30

From Robertson, S.M. et. al., Invest. Ophthalmol. Vis. Sci., Vol. 42, No. 4, Abs. 3004, S559, March 15, 2001

Responder Analysis: Black PatientsMean IOP in black patients at 4 PM, U.S. 12-month pivotal study

Responder AnalysisBlack Patients, IOP Change From Baseline

1 Year US Study, 8 AM

0

10

20

30

40

50

60

70

80

>7 >8 >9 >10mm Hg Decrease From Baseline

% of Black Patients



1 Year US Study, 10 AM

01020304050607080

>7 >8 >9 >10

mm Hg Decrease From Baseline

% of Black Patients



1 Year US Study, 4 PM

0

10

20

30

40

50

60

>7 >8 >9 >10

mm Hg Decrease From Baseline

% of Black Patients


54.7

49.6

39.0

35

45

55

65


% P

atie

nts

Resp

ondi

ng

*

* Significantly greater than latanoprost (p 0.043) and timolol (p< 0.0001).Adapted from Netland, P.A., et. al, American Journal of Ophthalmology, 2001; 132:472-484

Responder AnalysisIOP reduction 30% or mean IOP 17 mm Hg,

U.S. 12-month study, pooled visits

*

* Significantly greater than latanoprost (p 0.043) and timolol (p< 0.0001).Adapted from Netland, P.A., et. al, American Journal of Ophthalmology, 2001; 132:472-484

8.6

13.5

22.5

0

5

10

15

20

25

Non-Responder AnalysisLess than 3 mmHg change, U.S. 12-month study, 4 PM

% P

atie

nts

Not R

espo

ndin

g


Netland, P.A., et. al, American Journal of Ophthalmology, 2001; 132:472-484

54

80

91

45

73

87

36

62

82

0102030405060708090

100

<22 mmHg <20 mmHg <18 mmHg

% P

atie

nts

Res

pond

ing

at 4

PM

Travoprost 0.004% (n=197) Latanoprost 0.005% (n=193) Timolol 0.5% (n=195)

More patients respond to travoprostU.S. 12 Month Study, All patients, Mean IOP at 4 PM

91

80

54

87

73

45




% P

atie

nts

Resp

ondi

ng a

t 4 P

M

20

30

40

50

60

70

80

90

100

Responder Analysis: Travoprost vs. Latanoprost Mean IOP at 4 PM, U.S. 12-month pivotal study



Timolol 0.5%(n = 155)

Responder Analysis: Non-black PatientsMean IOP at 4 PM, U.S. 12-month pivotal study

Mean IOP (mmHg)

8784

72

63

4437

89

78

51


% P

atie

nts

Resp

ondi

ng a

t 4 P

M

20

30

40

50

60

70

80

90

100

International 9-month Pivotal Study Design

• Prospective, double-masked, parallel, randomized• Qualifying baseline IOP

– 24 to 36 mmHg at 9 AM– 21 to 36 mmHg at 11 AM and 4 PM

• Travoprost 0.004% q.d. administered at 9 PM in each eye. Timolol 0.5% b.i.d. administered at 9 AM and 9 PM

• IOP measurements at 9 AM, 11 AM, and 4 PM• Clinical assessments at 0.5, 1.5, 3, 4.5, 6, and 9 months• 573 patients randomised at 61 sites in Europe and Australia

Travoprost DemographicsInternational 9-month pivotal study

Iris ColorBROWNHAZELGREENBLUEGREY

RaceCAUCASIANBLACKASIANOTHER

Travoprost 0.004%

N %

194 98.52 1.01 0.50 0

70 35.524 12.212 6.179 40.112 6.1

Timolol0.5%

N %

181 97.82 1.12 1.10 0

59 31.923 12.413 7.074 40.016 8.6

p value

0.92

0.85

Powerful IOP Reduction from BaselineMean IOP change at 9 AM*, multi-national 9-month study

-10

-8

-6

-4

-2

0

0 0.5 1.5 3 4.5 6 9Months

Mean

IOP

Chan

ge (m

mHg

) Travoprost 0.004%(n = 197)

Adapted from Goldberg, I., J. Glaucoma, 2001, 10(5), 414-422* 12 hrs post dose

Baseline IOP of 27.1 mm Hg

18

20

22

24

26

28

Baseline 0.5 1.5 3 4.5 6 9

Months

Mea

n IO

P (m

m H

g)

Consistently Low Mean IOP Mean IOP at 9 AM*, international 9-month pivotal study


Adapted from Goldberg, I., J. Glaucoma, 2001, 10(5), 414-422* 12 hrs post dose

16

18

20

22

24

26

28

Baseline 0.5 1.5 3 4.5 6 9Months

Mea

n IO

P (m

m H

g)


Adapted from Goldberg, I., J. Glaucoma, 2001, 10(5), 414-422

Consistently Low Mean IOP Mean IOP at 11 AM*, multi-national 9-month pivotal study

* 14 hrs post dose

16

18

20

22

24

26

Baseline 0.5 3 9

Mea

n IO

P (m

m H

g)


MonthsAdapted from Goldberg, I., J. Glaucoma, 2001, 10(5), 414-422

Consistently Low Mean IOP Mean IOP at 4 PM*, multi-national 9-month pivotal study

* 20 hrs post dose

-10

-8

-6

-4

-2

0

0.5 1.5 3 4.5 6 9 12 15 18 21 24 27 30 33 39Month

Data on file. Alcon Labs, Inc. Baseline of 27.1 mm Hg

Travoprost Long Term StudyIOP Change From Baseline at 9 AM

Mea

n IO

P (m

mHg

) Cha

nge

(n=49)Travoprost 0.004%

63.3

47.1

35

45

55

65

Travoprost 0.004% Timolol 0.5%

% P

atie

nts

Resp

ondi

ng

Trav vs Tim*p<0..0001

*


More Patients Respond to TravoprostMulti-national 9 month Pivotal Trial, IOP reduction 30% or mean IOP 17 mmHg

Minimal Ocular Side Effects With TravoprostInternational 9-month pivotal study

• Cosmetic side effects common with prostaglandin analogues

• Mild hyperemia– Subsides over time– Only 2% of patients discontinued due to hyperemia– 32.5% did report some conjunctival hyperemia

• Eyelash changes: low incidence of complaints (1.5%)• Iris color changes: minimally observed (3.6%)• None believed to pose safety concerns

0.5 1.5 3 4.5 6 9

Mild HyperemiaMulti-national 9-month pivotal study

Hyperemia with travoprost 0.004% is consistently rated <0.63Severe

2Moderate

1Mild

0None/Trace

Months


Ocul

ar h

yper

emia

sca

le

No Serious Adverse EventsInternational 9-month pivotal study

Clinical trials of travoprost 0.004% q.d. found:

• No cystoid macular edema• No significant worsening of the visual field• No significant changes in corneal

thickness or corneal endothelial cell morphology

• No clinically significant blood chemistry abnormalities

Travoprost Effective as Adjunct to TimololMean IOP change at 8 AM, U.S. 6-month adjunctive therapy study

Travoprost (n=145)

TimololBaseline

0.5 1.5 3 4.5 6Study Visits (Months)

Mea

n IO

P Re

duct

ion

From

Bas

elin

e (m

mHg

)

-8

-7

-6

-5

-4

-3

-2

-1

0

Adapted from Orengo-Nania, S., et. al, American Journal of Ophthalmology, 2001, 132(6) 860-868

-8

-7

-6

-5

-4

-3

-2

-1

0

TimololBaseline

0.5 1.5 3 4.5 6

Months

Mea

n IO

P C

hang

e (m

mH

g)

Travoprost (n=145)Placebo (n=139)

Travoprost Effective as Adjunct to TimololMean IOP change at 8 AM, U.S. 6-month adjunctive therapy study

Adapted from Orengo-Nania, S., et. al, American Journal of Ophthalmology, 2001, 132(6) 860-868

Travoprost Efficacy Trials: Overview• Across studies mean IOP reductions up to 9

mmHg (33%)• Greater or equal efficacy compared with

latanoprost 0.005%• Greater efficacy compared with timolol 0.5% b.i.d.• Also proven effective as adjunctive therapy

Treatment % n Total n

Travoprost 0.004% 39.5% 259 656

Latanoprost 0.005% 27.6% 54 196

Timolol 0.5% 10.2% 74 727

Vehicle 2.5% 2 79

Overall Incidence of HyperemiaSummary of 2 U.S. and 1 multi-national pivotal study (averaged values)

Data on File, Alcon Laboratories Inc.

Minimal Ocular Side Effects With Travoprost

• Cosmetic side effects common with prostaglandin analogues

• Mild hyperemia– Subsides over time– Less than 3% of patients discontinued due to hyperemia– 35-50% did report some conjunctival hyperemia (range)

• Eyelash changes: low incidence of complaints (0.8%)

• Iris color changes: minimally observed (2-3%)• None believed to pose safety concerns

Mild Hyperemia U.S. 12 Month Pivotal Study

Hyperemia with travoprost 0.004% (n=197) is consistently rated <0.5(12 hours post dose) 3

Severe

2Moderate

1Mild

0None/TraceOc

ular

hyp

erem

ia s

cale

Months0.5 1.5 3 4.5 6 9 12

Adapted from Netland, P.A., et. al, American Journal of Ophthalmology, 2001; 132:472-484

No Serious Related Adverse EventsOverall

Clinical trials of travoprost 0.004% q.d. found:

• No clinically relevant worsening of the visual field• No clinically relevant changes in corneal thickness

or corneal endothelial cell morphology• No clinically relevant blood chemistry abnormalities

HyperemiaPatients With 2+ Scores

0

5

10%

of P

atie

nts

0.5 1.5 3

Months


3Severe

2Moderate

1Mild

0None/Trace

Study C-97-71, Data on file

TRAVATAN® Solution Hyperemia Response in the First Week of Treatment

Study C-01-52

-0.2

00.2

0.4

0.6

0.81

1.2

1.4

Screening 3 7

Days

Hyp

erem

ia S

core

No Prior Use ofProstaglandinAnalogue

Prior Use ofProstaglandinAnalogue

Percentage of patients complaining of hyperemia by telephone

15.4

7.8

3.2

02468

1012141618

% o

f pat

ient

s

Lumigan* TRAVATAN® Xalatan*

Stewart. et al., Survey Assesses Red Eye And Prostaglandin Use; Review of Ophthalmology, April 2002* Trade marks are property of their respective owners

Ophthalmic Solution

Percentage of patients requiring an extra office visit due to hyperemia

19.2

6.1

2.5

02468

101214161820

% o

f pat

ient

s

Lumigan* TRAVATAN® Xalatan*

Stewart. et al., Survey Assesses Red Eye And Prostaglandin Use; Review of Ophthalmology, April 2002* Trade marks are property of their respective owners

Ophthalmic Solution

No Difference in Plasma Concentrations of Travoprost Free Acid in Normal Subjects or

Hepatic Impaired Patients

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.1

0 1Normal Class A Class B Class C

Hepatic Impairment Group

Plas

ma

AL-

5848

Cm

ax (

ng/m

L)

Normal - Day 1Normal - Day 7Class A - Day 1Class A - Day 7Class B - Day 1Class B - Day 7Class C - Day 1Class C - Day 7

CHILDS-PUGHCLASS

HEPATICIMPAIRMENT

GROUPN

N Normal 6

A Mild 6

B Moderate 7

C Severe 5C

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Normal Mild Moderate Severe

Renal Impairment Category

Plas

ma

AL-

5848

Cm

ax (n

g/m

L)

Normal-Day 1Normal-Day 7Mild-Day 1Mild -Day 7Moderate-Day 1Moderate-Day 7Severe-Day 1Severe-Day 7

No Difference in Plasma Concentrations of Travoprost Free Acid in Normal Subjects or Renal

Impaired Patients

RenalImpairment

GroupN

CreatinineClearance

(mL/min/1.73 m2)Normal 6 Greater than 80

Mild 6 50-80

Moderate 6 30-49

Severe 6 20-29

Visits With Mean Pressures < 18 mm Hg

Per Protocol analysis

Number of Visits Where Mean IOPs < 18 mm HgTravoprost

0.004%Latanoprost

0.005% Timolol 0.5%

U.S. 1 YearStudy 8/18 0/18 0/18

International 9Month Study 9/15 NA 0/15

From Netland, P.A., et. al, American Journal of Ophthalmology, 2001; 132:472-484 andGoldberg, I., J. Glaucoma, 2001, 10(5), 414-422

Distribution of patients with IOP< 18 mm Hgat all 4 PM visits post-dose*

Latanoprost33%

Travoprost45%

Timolol22%

N=108 out of 585 patientsC-97-71, Data on File*20 hours post-dose for travoprost and latanoprost, 8 hours post-dose for timolol

Bimatoprost Responder Rates10 AM

36

52

64

7582

88

2028

37

50

61

74

0

20

40

60

80

100

15 16 17 18 19 20

IOP Target (mm Hg)

Res

pond

er ra

tes

%

bimatoprost 0.03%timolol 0.5%

Lumigan advertisement in Archives of Ophthalmology, Aug 2001, p 108 A-D

Responder Ratio vs. Timolol10 AM

11.21.41.61.8

22.22.42.6

15 16 17 18 19 20

IOP Target (mm Hg)

Res

pond

er ra

tio v

s. ti

mol

ol

bimatoprost 0.03%timolol 0.5%

Lumigan advertisement in Archives of Ophthalmology, Aug 2001, p 108 A-D

Travoprost Responder Rates10 AM

15

29

43

57

70

80

714

26

38

51

64

0102030405060708090

15 16 17 18 19 20

IOP Target (mm Hg)

Res

pond

er ra

tes

%

travoprost 0.004%timolol 0.5%

Data on File, Alcon Laboratories Inc., C-97-71

11.21.41.61.8

22.22.42.6

15 16 17 18 19 20

IOP Target (mm Hg)

Resp

onde

r rat

io v

s. ti

mol

ol

travoprost 0.004%bimatoprost 0.03%timolol 0.5%


‡*

* travoprost data from C-97-71, Data on File, Alcon Laboratories Inc.,‡ bimatoprost data from Lumigan advertisement in Archives of Ophthalmology, Aug 2001, p 108 A-D

Latanoprost Responder Rates10 AM

13

23

35

50

64

76

714

26

38

51

64

0102030405060708090

15 16 17 18 19 20

IOP Target (mm Hg)

Res

pond

er ra

tes

%

latanoprost 0.005%timolol 0.5%

Data on File, Alcon Laboratories Inc., C-97-71


11.21.41.61.8

22.22.42.6

15 16 17 18 19 20

IOP Target (mm Hg)

Res

pond

er ra

tio v

s. ti

mol

ol

travoprost 0.004%bimatoprost 0.03%latanoprost 0.005%timolol 0.5%

‡*

*

* travoprost and latanoprost data from C-97-71, Data on File, Alcon Laboratories Inc.,‡ bimatoprost data from Lumigan advertisement in Archives of Ophthalmology, Aug 2001, p 108 A-D

TRAVATAN® Study C-97-02Diurnal Control Over 24 Hours

Mean IOP

16

1820

22

2426

28

Baseline at8 AM

8 AM 10 AM 12 PM 4 PM 8 PM

Time of Day

IOP

(mm

Hg) Travoprost 0.004% (n=48)

Study DesignStudy C-01-24

Screening

WashoutUp to 4 Weeks

Eligibility

IOP Baseline Measurements at 8 AM,

12 PM, 4 PM, 8 PM, 12 AM, 4 AM, 8 AM

Dispense travoprost

0.004%

2 weeks on travoprost

0.004%

Dose travoprost 0.004%at 8 PM

Measure IOP after dose

IOP Measurements every 4 hours for 36 hours and then at

60 hours and 84 hours

Qualifying IOPStudy C-01-24

· Mean IOP 24 to 36 mm Hg at 8 AM.· Mean IOP 21 to 36 mm Hg at 12 PM (noon) on the Eligibility Visit.· The mean IOP is the average of two (2) IOP measurements in the

same eye.· The same eye(s) must qualify at all timepoints [8 AM (Saturday),

12 PM (Saturday) and 8 AM (24 hours/Sunday)] on the Eligibility Visit.

· The mean IOP in either eye at any timepoint not greater than 36 mm Hg.

Travoprost DemographicsStudy C-01-24

N % N %

AGE IRIS COLOR

<65 12 57.1 Brown 11 52.4

65 9 42.9 Hazel 5 23.8

SEX Blue 5 23.8

Male 7 33.3 DIAGNOSIS

Female 14 66.7 Open AngleGlaucoma 21 100

RACECaucasian 14 66.7

Black 7 33.3

Study C-01-24 Diurnal BaselinesMean Baseline IOP Over 24 Hours

0

5

10

15

20

25

30

8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM 4:00 AM 8:00 AM

Time of Day

Mean

IOP

(mm

Hg)

Baseline mmHg

Diurnal BaselinesMean Baseline IOP Over 24 Hours

0

5

10

15

20

25

30

8:00AM

12:00PM

4:00PM

8:00PM

12:00AM

4:00AM

8:00AM

Time of Day

Mea

n IO

P (m

m H

g)

0

5

10

15

20

25

30

0 4 8 12 16 20 24 28

Hours Post Dose

Mea

n IO

P (m

m H

g)

TravoprostConsistent Diurnal IOP Control

Study C-01-24

8 PM(Day 14)

H.B. Dubiner Travatan Administration Results in Effective Diurnal Reduction in Intraocular Pressure Over 36 Hoursand Lower Pressures Up to 3.5 Days Without Further Dosing; Presented at ARVO Meeting; May 2002

Diurnal Control Following Travoprost Administration First 24 Hours Post Dose

0

5

10

15

20

25

30

8:00PM

12:00AM

4:00AM

8:00AM

12:00PM

4:00PM

8:00PM

Time of Day

Mea

n IO

P (m

m H

g)

0

5

10

15

20

25

30

12 36 60 84

Hours Post Dose

Mea

n IO

P (m

m H

g)

Travoprost 0.004%

Travoprost - Long Duration of Effect After Discontinuation of Dosing

Study C-01-24, Mean IOP At 8 AM Visits

H.B. Dubiner Travatan Administration Results in Effective Diurnal Reduction in Intraocular Pressure Over 36 Hoursand Lower Pressures Up to 3.5 Days Without Further Dosing; Presented at ARVO Meeting; May 2002

Travoprost - Long Duration of Effect Mean IOP - 28-84 Hours After Instillation of Last Dose

0

510

15

2025

30

28 32 36 60 84Hours Post Dose

Mea

n IO

P (m

m H

g)

-20

-15

-10

-5

0

12 36 60 84

Hours Post Dose

IOP

Chan

ge fr

om B

asel

ine

(mm

Hg)

TRAVATAN

Travoprost - Long Duration of Effect After Discontinuation of Dosing

IOP Change From Baseline At 8 AM Visits

Travoprost - Long Duration of Effect Mean IOP Change From Baseline After Instillation of Last Dose

8 AM Visits

-20

-15

-10

-5

0

12 36 60 84Hours Post Dose

IOP

Cha

nge

From

B

asel

ine

(mm

Hg)

p=0.0001 for IOP change from baseline at all points

Diurnal IOP Fluctuation in Glaucoma Patients

11

7.6

3.7 3.6

0

2

4

6

8

10

12

POAG OffTreatment

POAGControlled

Normal Eyes Travoprost0.004%

IOP

Fluc

tuat

ion

(mm

Hg)

Drance SM. Arch Ophth, 1963;70: 302-311 Drance SM. Arch Ophth, 1960; 64: 494-501 H.B. Dubiner Travatan Administration Results in Effective Diurnal Reduction in Intraocular Pressure Over 36 Hoursand Lower Pressures Up to 3.5 Days Without Further Dosing; Presented at ARVO Meeting; May 2002

Drance SM Dubiner HB

Travoprost therapy results in a narrow range of diurnal IOP fluctuation

0

2

4

6

8

10

12

14

12% Stable VF 43% Stable VF Travoprost 0.004%

Mea

n IO

P Ra

nge

(mm

Hg)

Asrani, et al., 2000, Large Diurnal Fluctuations in Intraocular Pressure Are an Independent Risk Factor in Patients With Glaucoma, J. Glaucoma, 9, 134-142H.B. Dubiner Travatan Administration Results in Effective Diurnal Reduction in Intraocular Pressure Over 36 Hours and Lower Pressures Up to 3.5 Days Without Further Dosing; Presented at ARVO Meeting; May 2002

Quartile with Highest IOP

Range

Quartile with Lowest IOP

Range

Dubiner HBAsrani, et al.

Study DesignStudy C-01-103

Screening

WashoutUp to 4 Weeks

Eligibility

IOP Baseline Measurements at 8 AM,

12 PM, 4 PM, 8 PM, 12 AM, 4 AM, 8 AM

Dispense travoprost 0.004%

or latanoprost 0.005%

2 weeks ontravoprost

0.004%or latanoprost

0.005%

Dose travoprost 0.004%

or latanoprost 0.005% at 8 PM

Measure IOP before dose

IOP Measurements every 4 hours for 44 hours

C-01-103, Alcon Data on File

12

15

18

21

24

27

8am 12pm 4pm 8pm 12am 4am 8amTime

Mea

n IO

P (m

m H

g)

travoprost 0.004% latanoprost 0.005%


Equivalent Baseline Diurnal IOP ValuesTravoprost vs Latanoprost

Study C-01-103

12

13

14

15

16

17

18

8am 12pm 4pm 8pmTime

Mea

n IO

P (m

m H

g)



Diurnal IOP Control Travoprost vs Latanoprost

Study C-01-103

-11-10

-9-8-7-6-5-4-3-2-10


Mean

IOP

Chan

ge (m

m H

g)


Travoprost - 24 Hours Post DoseIOP Change from Baseline

Study C-01-103

3.3 mmHg

* p=0.0062

*

13

14

15

16

17

18

19

20

12 24 36 44Hours Post Dose

Mea

n IO

P (m

m H

g)



Extended IOP Control Travoprost vs Latanoprost

Study C-01-103

Normal SubjectsIOP Change (Morning Dosing, 8 AM Visits)

-6

-5

-4

-3

-2

-1

0

2 3 4 7

Treatment Day

IOP

Cha

nge

(mm

Hg)

Travoprost 0.004%

*8 AM Dosing Study C-00-56, U.s. Japanese Subjects, Alcon Data on file

Mexico 3-month Study Design

• Prospective, multi-center, open-label• Qualifying baseline IOP

– 24 to 36 mmHg at 8 AM

• Travoprost 0.004% q.d. administered at 8 PM in each eye.

• IOP measurements at 8 AM

• Clinical assessments at 0.5, 1, 2, 3 months

Demographics Mexico 3-month study

Travoprost0.004%

N %

RACEMestizo 30 100

AGE<65 19 63.3>65 11 36.7

GENDERMale 12 40

Female 18 60IRIS COLOR

Brown 28 93.3Green 2 6.7

DIAGNOSISOcular

Hypertension20 66.7

Open AngleGlaucoma

10 33.3

-10-9-8-7-6

-5-4

-3-2-1

0

Baseline Week 2 Month 1 Month 2 Month 3

Mea

n IO

P C

hang

e (m

mH

g)Travoprost Effective in Mestizo Population

Mexico Study (8 AM)IOP Change From Baseline

15

17

19

21

23

25

27

29


Mea

n IO

P(m

mH

g)Travoprost Effective in Mestizo Population

Mexico Study (8 AM)Mean IOP

-35

-30

-25

-20

-15

-10

-5

0


% C

hang

e Fr

om B

asel

ine

Travoprost Effective in Mestizo PopulationMexico Study (8 AM)

Percent Change From Baseline

Latanoprost 0.005%• Dosed once per day (less effective BID)• Causes mild hyperemia, iris color change, hypertrichosis,

and pruritis• Associated with perioperative CME and reactivation of

dormant HSV keratitis • Requires refrigeration before opening; discard 6 weeks

after opening• Degrades in the presence of heat and/or light

– Especially sensitive to Ultraviolet B

Unoprostone isopropyl 0.15%• IOP lowering efficacy < timolol, similar to TCAI• Pro-drug whose free acid is a weak FP receptor agonist • Mechanism of action is not fully understood• Dosed BID• Does not require refrigeration• May cause less iris color change and eyelash growth

Bimatoprost 0.03%• IOP lowering at QD dosing appears equal or superior (2-3 mm Hg)

to timolol 0.5% BID• Like latanoprost and travoprost, side effects include hyperemia,

eye color change, eyelash growth and pruritus• Less effective dosed BID than QD• Does not require refrigeration• Concentration 6-8 times > latanoprost or travoprost• CME and liver enzyme abnormalities reported during Phase III

trials.• Tolerability < other PGA ‘s (more hyperemia, pruritis, pain)

Travoprost 0.004%• IOP lowering efficacy at QD dosing is

– statistically significantly > timolol 0.5% BID (~2 mm Hg)– = or > latanoprost 0.005% QD– greater in black patients than non-black patients

• Like latanoprost and bimatoprost, side effects include hyperemia, eye color change, and eyelash growth

• Excellent stability profile: refrigeration not required• Less effective dosed BID than QD• No clinically significant blood chemistry abnormalities.

TRAVATAN: Formulation/Packaging

Novel FormulationShelf life and storage

• No refrigeration required, but can be refrigerated if desired

• Light stable• Stable to high temperature• Stable to freezing

TRAVATAN Solution XALATAN* LUMIGAN*

Degr

ees

Fahr

enhe

it

20

30

40

50

60

70

80

StabilityTemperature storage range of prostaglandin analogue products

*Trademarks are the property of their respective owners.

36F - 77 F

36F - 46 F

59F - 77 F


TRAVATAN Solution XALATAN* LUMIGAN*

Degr

ees

Fahr

enhe

it

20

30

40

50

60

70

80

StabilityTemperature storage range of prostaglandin analogue products


2C - 25C

2C - 8C

15C - 25C


Room Temperature Stability of Travoprost25 C (77 F)

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14 16 18 20 22 24

Months

% o

f Lab

el C

once

ntra

tion

Lot 20446F Unpouched

Lot 20446F Pouched

Linear (Lot 20446FUnpouched)

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14Time (Weeks)

% o

f Lab

el (T

ravo

pros

t or L

atan

opro

st )

TRAVATAN®solution (Pouched)

TRAVATAN®solution (Unpouched)

Xalatan*

Linear (Xalatan*)

Linear(TRAVATAN®solution (Pouched))Linear(TRAVATAN®solution (Unpouched))


High Temperature StabilityMarketed samples at 55C (131F)†

®

®

†12 week exposure at 55C is approximatelyequivalent to 2 yrs at room temperature

Refrigerated StabilityTravoprost at 4°C (39°F)

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80 90

Weeks

% o

f Lab

el C

once

ntra

tion

Lot 13927-02 Lot 13928-02 Lot 14338-01

Freeze-Thaw StabilityTravoprost Repetitive Freeze-Thaw -20°C to 30°C (-4°F to 86°F)

0

20

40

60

80

100

120

0 1 2 3 4 5 6

Freeze Thaw Freeze Thaw Freeze Thaw

Weeks

% o

f Lab

el C

once

ntra

tion

Batch 20448F - Lot 15175-02

Linear (Batch 20448F - Lot15175-02)

Photostability of TravoprostAccelerated Photostability Testing of Marketed Samples at 25C (77F)

ICH Regulated Light Exposure Conditions†

0

20

40

60

80

100

120

0 1 2 3 4Time (Weeks)

% o

f Lab

el (L

atan

opro

st o

r Tra

vopr

ost)

TRAVATAN®solution (Pouched)TRAVATAN®solution (Unpouched)Xalatan*


†4 weeks at this condition equivalent to 2 years normal room lighting

®

®

Novel Packaging

Number of daysof therapy

Product

Label

Average dropsize

Total dropsper container

TRAVATAN® Solution

2.5 mL

26 L

111

55.5

LUMIGAN*

2.5 mL

32 L

99

49.5

XALATAN*

2.5 mL

31 L

78

39


Storage of TRAVATAN® Solution

• No refrigeration required, but can be refrigerated if desired– Can be stored at room temperature

• Does not require protection from light • Stable at 40C for up to 6 months

Patents· L.W. Schneider, 1997, Storage-stable prostaglandin compositions, US Patent 5,631,287· L.W. Schneider, 1998, Storage-stable prostaglandin compositions, US Patent 5,849,792· L.W. Schneider, R. Bawa, A.L. Weiner, 2000, Storage-stable prostaglandin compositions, US Patent 6,011,062· A.L. Weiner, S.C. Airy, C. Yarborough, J.A. Clifford, W.E. McCune, 2001, Prostaglandin Product, U.S. Patent

6,235,781

Novel Packaging

Uniformity of dose•New DROP-TAINER® dispenser •Uniform dropsize (~26 µL)•Dispensing is easy, without streaming•Patented polypropylene bottle

EU cap US cap

Novel Packaging• TRAVATAN® solution is packaged in a foil pouch • The pouch provides a controlled stability of the

active agent and an extended expiry period for the packaged product

• Unpouched TRAVATAN® is physically and chemically stable over a broad range of temperature storage conditions, including exposure to light

• It is perfectly safe for anyone to handle the TRAVATAN® carton, pouch and bottle

• There are no adequate well-controlled studies in pregnant women for any of the available prostaglandin analogue products

• All of the ophthalmic prostaglandin analogue products have a Pregnancy Category: C rating (U.S. FDA)

• Due to the known reproductive related actions of prostaglandins and their analogues, Alcon chose stricter labeling for use in pregnant women - these additional statements were not required by the FDA

• Although the risk is minimal, Alcon believes that all ophthalmic prostaglandin analogue products should be handled carefully by pregnant women or by women who are attempting to become pregnant. Pregnant women should wash their skin with soap and water if they come into contact with any ophthalmic prostaglandin analogue product

TRAVATAN Solution and Pregnancy

TRAVATAN®

(travoprost 40 micrograms/ml eye drops)

Once-Daily TRAVATAN®

(travoprost ophthalmic solution) 0.004%

Date post:	12-Apr-2017
Category:	Health & Medicine
Upload:	michael-duplessie
View:	16 times
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