mentofGlaucomaSAFLUTANModule3v6

1
Preservative-Free Solutions in the
Treatment of Glaucoma
Profile of SAFLUTAN™† (tafluprost)
†SAFLUTAN is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

2
Introduction
 Preservative-free formulations of glaucoma medications may have a
positive impact on ocular health
 Minimizing damage to the ocular surface by using a preservative-free
formulation may improve patient comfort and increase compliance
 Tolerability issues may affect quality of life and lead to nonadherence
 Comprehensive management of glaucoma needs to include IOP-
lowering efficacy as well as long-term safety
 SAFLUTAN™† (tafluprost) is the first preservative-free prostaglandin that
reduces IOP effectively and is associated with a high degree of patient
comfort, which may promote compliance
IOP = intraocular pressure

3
Learning Objectives
 Understand the differences between preserved and preservative-free
solutions, their impact on ocular health, and implications for the
management of glaucoma
 Review the efficacy profile of SAFLUTAN™† (tafluprost) to understand
its IOP-lowering effects, the extent to which these effects are maintained
over time, and how SAFLUTAN’s efficacy compares to that of
latanoprost
 Review the safety/tolerability profile of SAFLUTAN to understand its
effects on ocular health and symptoms and signs relative to latanoprost

4
BAK Concentrations of Select
Prostaglandin Analogues
0
0.01
0.02
0.03
Latanoprost
(Xalatan®)
Travoprost
(Travatan®)
Tafluprost
(SAFLUTAN™†)
Bimatoprost
(Lumigan®)
BAKConcentration(%)
BAK = benzalkonium chloride
Xalatan Prescribing Information. Pfizer Manufacturing, Puurs, Belgium.: 2009; Travatan Prescribing Information. http://rxlist.com/travatan-drug.htm.
Accessed March 11, 2009; Lumigan Prescribing Information. Allergan, Inc., Irvine, CA.: 2006; SAFLUTAN Summary of Product Characteristics.
Merck & Co., Inc., Whitehouse Station, NJ, USA.: 2008.

5
Preservative-Free Eye Drops:
Reduced Symptomsa
ap < 0.0001 for all comparisons between groups.
Jaenen N et al. Eur J Ophthalmol. 2007;17(3):341–349.
0
10
20
30
40
50
Pain or
discomfort
Foreign body
sensation
Stinging or
burning
Dry eye
sensation
Preserved
Preservative-free
Patients(%)
N = 9,658

6
Preservative-Free Eye Drops:
Reduced Signsa
ap < 0.0001 for all comparisons between groups.
Jaenen N et al. Eur J Ophthalmol. 2007;17(3):341–349.
0
10
20
30
40
50
60
Hyperaemia Blepharitis
(anterior/posterior)
Superficial punctate
keratitis
Fluorescein staining
Preserved
Preservative-free
Patients(%)
N = 9,658

7
Comprehensive
Glaucoma Management
Ocular
tolerability
Long-term
safety
Long-term
control
Patient
remaining
on therapy
IOP-lowering
efficacy

8
Profile of SAFLUTAN™† (tafluprost)
 SAFLUTAN™† (tafluprost) is a new prostaglandin analogue for the treatment of
glaucoma and is indicated for:
– Reduction of elevated IOP in open angle glaucoma and ocular hypertension
• As monotherapy in patients:
– Who would benefit from preservative-free eye drops
– Who are insufficiently responsive to first line therapy
– Who are intolerant or contraindicated to first line therapy
• As adjunctive therapy to beta-blockers
 SAFLUTAN is the first preservative-free prostaglandin
 SAFLUTAN is a highly potent and selective FP-receptor agonist
 SAFLUTAN reduces IOP effectively in animal models, healthy volunteers, and
glaucoma patients
 SAFLUTAN is associated with fewer adverse signs and symptoms than latanoprost,
the leading prostaglandin
 SAFLUTAN is associated with a high degree of patient comfort, which may
promote compliance
FP = prostaglandin F; IOP = intraocular pressure
SAFLUTAN Summary of Product Characteristics. Merck & Co., Inc., Whitehouse Station, NJ, USA.: 2008; Ophthalmol Times Eur. 2008;4(5):1;
Takagi Y et al. Exp Eye Res. 2004;78:767–776; Pisella PJ et al. Br J Ophthalmol. 2002;86:418–423; Ropo A et al. 4th International Congress on
Glaucoma Surgery; April 16–18, 2009, Geneva, Switzerland. Poster.

9
SAFLUTAN™† (tafluprost) Has High FP Receptor
Affinity: 12 Times Greater Than Latanoprost
Prostaglandin Receptor-Binding Affinity (Moles per Liter)a
Prostaglandin
Analogueb FP EP1 EP2 EP3 IP/DP TP
PGF2α 1.2× 10−8 3.2× 10−7 6.4× 10−6 1.6× 10−7 >10−4 > 10−4
Latanoprost acid 1.0× 10−8 5.0× 10−6 >10−4 2.8× 10−5 >10−4 > 10−4
Travoprost 3.5× 10−9 3.0× 10−8 >10−4 2.4× 10−5 >10−4 > 10−4
Bimatoprost 4.5× 10−9 6.5× 10−7 >10−4 >10−4 >10−4 3.4× 10−5
Tafluprost 0.5× 10−9 >10−6 >10−6 6.7× 10−8 >10−6 > 10−6
EC50 = half maximal effective concentration; FP = prostaglandin F; PGF2α = prostaglandin F2α
aReceptor binding assessed according to EC50 values.
bData refer to active drug product.
Stjernschantz JW. From PGF2α-isopropyl ester to latanoprost: a review of the development of Xalantan. Inv Ophthalmol Vis Sci. 2001;42(6):1134–1145;
Stjernschantz JW et al. Mechanism and clinical significance of prostaglandininduced iris pigmentation. Surv Ophthalmol. 2002;47(suppl 1):S162–S175;
Takagi Y et al. Exp Eye Res. 2004;78:767–776.
 Higher FP affinity has not been correlated with an increase in either efficacy or safety

10
 Preservative-free and preserved tafluprost similarly penetrate the aqueous humor
 BAK is not necessary for tafluprost to penetrate the cornea
Preserved vs Preservative-Free Tafluprost:
Equivalent Penetration
 N=48, as 6 groups of 8
 Preservative-free tafluprost 0.0015% in one eye and preserved tafluprost
0.0015% in the other eye
 Tafluprost acid concentration in aqueous humor assessed at 6 time points: 45
minutes and 1.5, 2, 3, 6, and 8 hours
Pharmacokinetic
Parameter
Preservative-Free
Tafluprost
Preserved Tafluprost
Cmax (ng/mL) 4.50 3.99
AUC3h (ng•h/mL) 5.14 4.54
AUC = area under curve; BAK = benzalkonium chloride; Cmax = maximum concentration
Reprinted with permission from Pellinen P et al. Ophthalmic Res. 2009;41:118–122.

11
Tafluprost Is Safe and Effective in
Healthy Human Volunteers
Study 1
 Phase I study of 16 healthy
volunteers
 Tafluprost at 0.0001%, 0.0005%,
0.0025%, and 0.005% versus
placebo
 Sequentially ascending doses
 Decrease in IOP was greater with
0.0025% and 0.005% tafluprost
than with 0.0001% tafluprost
 Tafluprost was generally well
tolerated
Study 2
 Phase I study of 49 healthy
volunteers
 Tafluprost at 0.0025% or 0.005%,
latanoprost at 0.005%, or placebo
 Once daily for 7 days
 IOP reduction was greater with
0.005% tafluprost than with 0.005%
latanoprost or placebo
 Tafluprost was generally well
tolerated
Sutton A et al. Int J Clin Pharmacol Ther. 2008;46:400–406.

12
Tafluprost and Latanoprost Reduce IOP
in Healthy Volunteers (Study 2)
ap < 0.05, bp < 0.01, cp < 0.001 for tafluprost (0.005%) versus placebo.
dp < 0.05, ep < 0.01 for tafluprost (0.005%) versus latanoprost.
fp < 0.005 for latanoprost versus placebo.
Adapted with permission from Sutton A et al. J Ocul Pharmacol Ther. 2007;23:359–365.
-8
-7
-6
-5
-4
-3
-2
-1
0
+1 +2 +4 +8 +12 +24 +12 +12 +12 +12 +12 +24 +1 +2 +4 +8 +12 +24
MeanChangeFromBaselineIOP(mmHg)
Tafluprost (0.0025%)
Tafluprost (0.005%)
Placebo
Latanoprost (0.005%)
Day 1 D2 D3 D4 D5 D6 Day 7
a,d
c b,d
b
b,d
b
a
a
c
a
a
f
f

13
Preservative Has No Influence on the Efficacy
of Tafluprost in an Open-Label Trial
14
16
18
20
22
24
26
IOP(mmHg)
p = 0.96
Week 1
8:00 12:00 16:00 20:00
Baseline
8:00 12:00 16:00 20:00
Week 4
8:00 12:00 16:00 20:00
Visit and Time
Preserved tafluprost (N = 42)
Preservative-free tafluprost (N = 43)
Adapted with permission from Hamacher T et al. Acta Ophthalmol. 2008;86(Suppl 242):14–19; Data on file, MSD ____.

14
Similar Efficacy and Safety of Tafluprost and
Latanoprost in Glaucoma Patients
 Methods
– 38 patients with open-angle glaucoma or ocular hypertension
– 6-week treatment with tafluprost (0.0015%) or latanoprost (0.005%)
 Results
– Mean IOP reduction was similar
• 33% for both groups
– IOP reduction was stable for 24 hours
– Adverse events were few and evenly distributed between groups
– Conjunctival hyperaemia: low incidence and mostly mild
 Conclusion
– IOP-lowering efficacy and safety profile of tafluprost are comparable to those
of latanoprost
Papadia M et al. Association for Research in Vision and Ophthalmology; April 30–May 4, 2006, Ft. Lauderdale, FL. Poster.

15
14
16
18
20
22
24
26
28
IOP(mmHg) Efficacy of
Tafluprost vs Latanoprost
p = 0.81
Data on file, MSD ____.
Day 7
8:00
Day 0
8:00 12:00 16:00 20:00
Day 42
8:00 12:00 16:00 20:00
Day 21
8:00
N = 36
Visit and Time
33%
Mean Reduction
From Baseline
Tafluprost
Latanoprost

16
Long-Term Study of Tafluprost:
Efficacy and Safety
 Long-term phase III study of tafluprost vs latanoprost
– Methods
• Patients with open-angle glaucoma or ocular hypertension
• 49 centers in 8 countries
• 6-month study extended to 24 months
– Primary outcome measure assessed at 6 months
• Tafluprost (0.0015%) or latanoprost (0.005%), once daily
– 533 patients randomized (n = 269 tafluprost; n=264 latanoprost)
– 420 patients continued into extension interval (n = 196 tafluprost; n = 224 latanoprost)
– After washout, patients were required to have an IOP of 22–34 mmHg in at least one eye
at baseline
• Key endpoint:
– Change in IOP from washout baseline

17
Sustained IOP Reduction Comparable to Latanoprost
Over 24 Months From a Washout Baseline
Double-masked, active-controlled, parallel-group, multinational, multicenter, 24-month
phase III study of tafluprost preserved form vs latanoprost
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
22.0
24.0
26.0
28.0
30.0
mmHg,Mean
Sustained IOP Control Over 24 Monthsa
Baseline Month 6 Month 12 Month 18 Month 24
Hours 8 12 16 20
Tafluprost (N = 185 at 24 months)
Latanoprost (N = 217 at 24 months)
b
b c c
8 12 16 208 12 16 208 12 16 208 12 16 20
CI = confidence interval; IOP = intraocular pressure; NS = not significant; RM ANOVA = repeated measurements of analysis of variance
aData based on 511 patients who had IOP measurements at 3 months or later.
bUpper 95% CI (RM ANOVA) was 1.54 and 1.70 at 6 and 12 months, respectively (p = NS compared to latanoprost).
cUpper 95 CI (RM ANOVA) was 1.33 and 1.44 at 18 and 24 months, respectively.

18
IOP Control Maintained Following Switch from Latanoprost to
SAFLUTAN™† (tafluprost)a in an Open-Label Trial
 Switching from preserved latanoprost to preservative-free SAFLUTAN
had no impact on IOP reduction
 IOP reduction maintained over the entire 12-week trial
aIn a 12-week, multinational, phase IIIb, open-label study evaluating changes in ocular signs and symptoms in patients switched from latanoprost to
preservative-free SAFLUTAN.
bPatients were diagnosed with open-angle glaucoma or ocular hypertension; used latanoprost ≥6 months and had ≥2 symptoms, or 1 sign and 1 symptom.
Ropo A et al. 4th International Congress on Glaucoma Surgery, Geneva, Switzerland, April 16–18, 2009.
30
29
28
27
26
20
19
18
17
16
15
14
13
12
10
0
2 weeks 6 weeks 12 weeks
Tafluprost (N = 158)
Latanoprost (N = 158)
MeanIOP(mmHG)
p < 0.001 p = 0.003 p = 0.33

19
Tafluprost Is Suitable for
Adjunctive Therapy
 Phase III study of 185 patients
– Primary open-angle glaucoma or ocular hypertension not controlled by
timolol monotherapy
 Tafluprost (0.0015%) or vehicle, once daily
– As adjunct to 0.5% timolol twice daily for 6 weeks
 Primary end point:
– Change from baseline in diurnal IOP at 6 weeks
 Tafluprost was superior to vehicle
– IOP reduction of ≥30% from baseline: 27% vs 14% for vehicle
– More ocular adverse events with tafluprost than with vehicle (42% vs 29%),
but most were mild
Egorov E et al. Eur J Ophthalmol. 2009;19:214–222.

20
In Vitro Effect of SAFLUTAN™† (tafluprost) on
Conjunctival Cells Was Most Similar to Salinea
 Immortalized human conjunctival cells were used in this analysis of preservative-free tafluprost’s effect
on cell membrane integrity
 Membrane integrity following treatment was 53% with BAK 0.005%, 43% with BAK 0.015%, and 37%
with BAK 0.02% vs control (p < 0.001 between treatments)
 It was noted that results obtained in an in vitro model could not be fully extrapolated to in vivo conditions
 The clinical relevance of these findings is unknown
BAK = benzalkonium chloride; PBS = phosphate-buffered saline
aIn vitro membrane integrity of human conjunctival epithelial cells after 30-minute exposure to PBS control, BAK 0.005%, BAK 0.015%, BAK 0.02%,
and preservative-free tafluprost.
bp < 0.05 vs control.
cp < 0.001 tafluprost vs latanoprost.
Adapted with permission from Brasnu E et al. Curr Eye Res. 2008;33:303–312.
0
20
40
60
80
100
CellMembraneIntegrity,%
Control
(PBS)
Tafluprost
91%b
100%
37%
Latanoprost

21
Use of Tafluprost With Timolol Provides
Additive Effects for Reduction of IOP
aMean (± standard error of the mean; SEM) diurnal IOP with tafluprost or vehicle, as adjunctive to timolol.
bVehicle in this study comprised the same formulation as SAFLUTAN, without the tafluprost ingredient.
Adapted with permission from Egorov E et al. Eur J Ophthalmol. 2009;19(2):214–222.
Randomized, double-masked, parallel-group, multinational, multicenter phase III open-label studya
10.0
11.0
12.0
13.0
14.0
15.0
16.0
17.0
18.0
19.0
20.0
21.0
22.0
23.0
24.0
25.0
26.0
27.0
28.0
29.0
30.0
DiurnalIOP(mmHg),Mean±SEM
Timolol + SAFLUTAN™† (tafluprost) (N = 96)
Timolol + vehicle (N = 89)b
Patients switched to concomitant
SAFLUTAN from concomitant vehicle
8 10 16 8 10 16 8 10 16 8 10 16 8 10 168
Baseline
Screening
(4-week timolol run-in)
Week 2 Week 4 Week 6 Week 8 Week 12
At Week 6,
all patients
received
tafluprost
Double-Masked Open-Label
Hours
p < 0.001 at 6 weeks (primary end point)

22
0
10
20
30
40
50
60
70
80 Latanoprost (Baseline; N = 158)
SAFLUTAN (Week 12; N = 158)
Irritation/ burning/
stinging
Itching Foreign body
sensation
Tearing
PatientsWithAbnormalValues,%
Fewer Ocular Symptoms with SAFLUTAN™†
(tafluprost) Compared to Latanoprosta
 SAFLUTAN provided dramatic reduction in ocular symptoms across
each category vs latanoprost
 Improvements seen at Week 12
Ocular Symptomsb,c
(p < 0.001)
Dry eye sensation
cSymptoms reported as mild in severity were considered abnormal.

23
 SAFLUTAN provided dramatic reduction in ocular signs across each
category vs latanoprost
 Improvements seen at Week 12
Fewer Ocular Signs for SAFLUTAN™† (tafluprost)
Compared to Latanoprosta,b
cBaseline vs 12 weeks; p < 0.001.
dBaseline vs 12 weeks; p < 0.003.
0
10
20
30
40
50
60
70
80
90
100 Baseline (latanoprost)
After 12 weeks of treatment
with preservative-free tafluprost
Tear-film
break-up
time
Corneal
fluorescein
staining
Conjunctival
fluorescein
staining
Conjunctival
hyperaemia
Patients(%)
Blepharitis Tear
production
c
c c
c
c
d

24
Preservative-Free Tafluprost Causes Less
Cellular Distress Than Latanoprost
 In vitro study designed to quantify the degree to which prostaglandin
analogue formulations induce oxidative stress and apoptosis in human
conjunctival cells
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Oxidative Stress
Apoptotic Effects
DistressRatio
(RelativetoControl)
c
Control (PBS) Tafluprost Latanoprost
(0.02% BAK)
0.02%
BAK
d
e
d
e
aOxidative stress was measured via a probe for hydroethidine, a marker of the superoxide anion.
bApoptotic effects were measured via a Yopro-1 probe, which allows for quantification of P2X7 cell death receptor activation.
cp < 0.05 compared with control with the Yopro test.
dp < 0.001 vs control with hydroethidine test.
ep <0.001 vs control with Yopro-1.
Adapted with permission from Brasnu E et al. Curr Eye Res. 2008;33(4):303–312.
a
b

25
Summary
 Management of glaucoma is multifactorial
 Tolerability problems and administration difficulties associated with
glaucoma medications may affect QOL and lead to eye drop
discontinuation and poor medical outcomes
 SAFLUTAN™† (tafluprost) is the first preservative-free prostaglandin
analogue and has a high affinity for FP receptors, which have been
demonstrated to be strong mediators of the IOP-lowering mechanism
 SAFLUTAN provides substantial, sustained IOP-lowering efficacy
FP = prostaglandin F; IOP = intraocular pressure; QOL = quality of life
Chawla A et al. Ophthalmol Scand. 2007;85(4):464; Schwartz GF. Curr Opin Ophthalmol. 2005;16(2)114–121; Pisella PJ et al. Ophthalmic Res.
2000;32:3–8; Jaenen N, et al. Eur J Ophthalmol. 2007;17(3):341–349; First preservative-free prostaglandin treatment approved. Ophthalmol Times
Eur. 2008;4(5):1; Takagi Y et al. Exp Eye Res. 2004;78:767–776; Papadia M et al. Association for Research in Vision and Ophthalmology; April 30–
May 4, 2006, Ft. Lauderdale, FL. Poster; Data on file, MSD ____.

26
Summary (cont)
 SAFLUTAN™† (tafluprost) does not compromise cell membrane integrity
 SAFLUTAN is associated with significantly fewer adverse reactions than
preserved latanoprost
 SAFLUTAN is safe and well tolerated
 Patient satisfaction is greater with SAFLUTAN compared to latanoprost
 SAFLUTAN provides a risk-benefit ratio that makes it a valuable option
for glaucoma patients
Brasnu E et al. Curr Eye Res. 2008;33:303–312; Ropo A et al. 4th International Congress on Glaucoma Surgery; April 16–18, 2009, Geneva,
Switzerland. Poster; Data on file, MSD ____; Sutton A et al. J Ocul Pharmacol Ther. 2007;23:359–365.

27
Preservative-Free Solutions in the
Treatment of Glaucoma
Before prescribing SAFLUTAN™† (tafluprost),
please read the full Prescribing Information.
Merck does not recommend the use of any product
in any different manner than as described in the
Prescribing Information.
Adapted with permission from Elsevier. Copyright © 2009.
Distributed with permission from Santen Pharmaceutical Co., Ltd.
Copyright © 2009 Merck & Co., Inc. All rights reserved.
07-10 RTG-2009-W-1289116-SS
Visit us on the World Wide Web at www.merck.com

29
Preservative-Free Tafluprost:
In Vivo Data
 24 rabbits total: 6 per group
– Preservative-free tafluprost
– Latanoprost (0.02% BAK)
– PBS (0.02% BAK)
– PBS (control)
 Results assessed at 4 hours and
Day 1 – Day 7, via:
– In vivo confocal microscopy
– Slit-lamp biomicroscopy
– Conjunctival impression cytology
– Flow cytometry
– Immunohistology
• CD45: marker of inflammation
• TUNEL: marker of apoptosis
1 drop
every 5
minutes;
15 times
total
BAK = benzalkonium chloride; PBS = phosphate-buffered saline; TUNEL = terminal deoxynucleotidyl transferase mediated dUTP (uridine 5′
triphosphate) nick end labeling
Liang H et al. Br J Ophthalmol. 2008;92:1275–1282.

30
Preservative-Free Tafluprost:
In Vivo Data
Evaluation of ocular surface abnormalities by in vivo confocal microscopy
ap < 0.0005 versus control (PBS).
bp < 0.0005 versus preservative-free tafluprost.
cp < 0.005 versus latanoprost.
Adapted with permission from Liang H et al. Br J Ophthalmol. 2008;92:1275–1282.
0
2
4
6
8
10
12
14
16
18
20
Control (PBS) Preservative-free
tafluprost
Xalatan (latanoprost;
0.02% BAK)
PBS with 0.02% BAK
4 Hours 1 Day
a, b
a, b, c
SurfaceAbnormalityScore

31
Sutton A et al. Int J Clin Pharmacol Ther. 2008;46:400–406.
Tafluprost Reduced IOP
in Healthy Volunteers
-5
-4
-3
-2
-1
0
0.0001% 0.0005% 0.0025% 0.005%
MaximalIOPComparedWithPlacebo(mmHg)
Tafluprost Concentration
Maximal Effects Seen After 12 Hours on Day 2 of Testing

32
Greater Patient Satisfaction With SAFLUTAN™†
(tafluprost) Compared to Latanoprost
 Greater patient satisfaction was seen in patients switching to preservative-free
SAFLUTAN than in patients receiving preserved latanoprost
 Patients were diagnosed with open-angle glaucoma or ocular hypertension, used
latanoprost ≥6 months, and had ≥2 symptoms or 1 sign and 1 symptom
0
10
20
30
40
50 Baseline (latanoprost)
After 12 weeks of treatment with
preservative-free tafluprost
Totally satisfied Very satisfied
Baseline vs 12 weeks
p < 0.001
N = 158
Patients(%)

33
Conjunctival Hyperaemia
With Prostaglandins
0
10
20
30
40
50
Xalatan
(latanoprost)
Travatan
(travoprost)
Lumigan
(bimatoprost)
Patients(%)
Xalatan Summary of Product Characteristics. Pfizer Manufacturing, Sandwich, Kent, UK.: 2007; Travatan Summary of Product Characteristics.
Alcon Laboratories, Hemel Hempstead, Hertfordshire, UK.: 2006; Lumigan Summary of Product Characteristics. Allergan Ltd, Marlow, Bucks, UK.:
2007. All available at: http://emc.medicines.org.UK/browsedocuments.aspx. Accessed May 30, 2009.

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