Transcript Lessons from the Ocular Hypertension Treatment Study (OHTS)

Evidence-Based Glaucoma Therapy
What is the Role of Medical Therapy in
Reaching Target Pressures?
XIV Jornadas Dr. Benjamin Boyd
Sociedad Panameña de Oftalmologia
Panama, R.P. 2003
Paul Palmberg, MD, PhD
Bascom Palmer Eye Institute, University of Miami
IOP-Lowering Agents
Drug Class
Proposed Mechanism of Action
Cholinergic agonists
Ciliary muscle contraction (facilitating
uveoscleral outflow and trabecular outflow)
2-Adrenergic agonists
Increasing trabecular outflow by a
mechanism that is not completely
understood
2-Adrenergic antagonists
Inhibition of aqueous production
by the ciliary epithelium
2-Adrenergic agonists
Inhibition of aqueous production
by the ciliary epithelium ± increasing
uveoscleral outflow
Carbonic anhydrase
inhibitors
Inhibition of aqueous production
by the ciliary epithelium
Prostaglandin F2
derivatives
Increased uveoscleral outflow
Adapted from Kaufman P. Presented at: Glaucoma in the 21st Century 2001.
Glaucoma Therapy June 2003
Major Clinical Trials Demonstrated Better Outcomes at
Lower Intraocular Pressures Than Previously Sought
 Ocular Hypertension (20% IOP reduction used, but lower better)
Ocular Hypertension Treatment Study (OHTS) 2002
 Mild, initial POAG (35% IOP reduction in CIGTS worked well)
Comparison of Initial Glaucoma Treatments Study (CIGTS) 2001
Early Manifest Glaucoma Treatment Study (EMGTS) 2002
 Normal Tension Glaucoma (30% IOP reduction recommended)
Collaborative Normal Tension Glaucoma Study (CNTGS) 1999
 Advanced POAG (35-50% reduction did best)
Advanced Glaucoma Intervention Study (AGIS) 2000
Antimetabolites in Filtering Surgery Study (AFSS) 2000
Meta-Analysis of Multiple Trials (UK,
Scandinavia and USA)
Percentage of patients reaching a specific target IOP
Diurnal IOP at
end of treatment
ratio
15 mm Hg
16 mm Hg
17 mm Hg
18 mm Hg
19 mm Hg
20 mm Hg
Latanoprost
(n=398)
Timolol
(n=318)
Odds
27
39
56
70
83
89
14
26
38
55
72
81
2.2*
1.8*
2.0*
1.9*
1.9*
1.9**
*P <0.001 (Pearson chi-square test) latanoprost vs timolol
**P <0.002 (Pearson chi-square test) latanoprost vs timolol
Pharmacia. Data on file.
Change in IOP From Baseline (mm Hg)
(Mean ± SEM)
Diurnal IOP Reduction at 3 Months
Timolol +
Dorzolamide
(n=90)
Latanoprost
(n=85)
0
-1
-2
-3
-4
-5
P=0.79
-6
Least Square Means (ANCOVA)
Emmerich KH. Graefes Arch Clin Exp Ophthalmol.
2000;238:19-23.
Emmerich KH, et al. AAO, New Orleans, USA, 1998.
Latanoprost vs Timolol in CACG
ITT population
% decrease in IOP from baseline
0
Week 6
Week 12
-5
-10
-15
-20
20%
20%
Latanoprost
Timolol
-25
-30
-35
30%
33%
Chew, on behalf of the EXACT Study Group (2001)
Latanoprost vs Timolol in CACG
ITT population
% patients
P<.002
80
70
Latanoprost
Timolol
P<.001
60
50
40
P<.001
30
20
10
0
15
16
17
18
19
IOP (mm Hg)
20
21
>21
Chew, on behalf of the EXACT Study Group (2001)
Latanoprost Efficacy in
Pigmentary Glaucoma
Change in IOP From Baseline (mm Hg)
(Mean ± SEM)
Diurnal IOP reduction
8
P<0.001
P<0.001
7
6
5
Latanoprost (n=18)
4
Timolol (n=18)
3
2
1
0
6 months
12 months
Mastropasqua L, et al. Ophthalmology, 1999;106:550-555.
Diurnal IOP Range and
Disease Progression
Relative risk* of disease progression within 5 years
6
5.76
Relative Risk
5
*The ratio between the
incidence of a disease
symptom among
individuals
with a given risk factor to
the incidence among
those without it.
4
3
2
1
1.00
0
Diurnal IOP Range Diurnal IOP Range
3.1 mm Hg
5.4 mm Hg
Asrani S, et al. J Glaucoma. 2000;9:134-142.
Latanoprost qd vs Dorzolamide tid
and Timolol bid Over 24 Hours
Circadian control of IOP
25
Baselin
e
Dorzolamide
tid
Timolol bid
23
21
19
17
Latanoprost
qd
15
13
0
3 PM
6 PM
9 PM Midnight 3 AM
6 AM
9 AM Noon
Time (Hours)
Orzalesi N, et al. Invest Ophthalmol Vis Sci. 2000;41:2566-2573.
Xalatan® (latanoprost ophthalmic solution)
Lumigan®† (bimatoprost ophthalmic solution)
Travatan®† (travoprost ophthalmic solution)
Richard Parrish, II, MD, Paul Palmberg, MD, PhD,
Wang-Pui Sheu, PhD, and the XLT Investigators
American Journal of Ophthalmology 2003; 135:688-703
OH
COOH
PGF2
CH3
OH
OH
10 years
Esterification
OH
COOCH(CH3)2
LATANOPROST
OH
Stjernschantz, IOVS, 2001
OH
Double bond
saturation
Phenyl
substitution
Latanoprost: hypothesized mechanism
of action
Latanoprost
Latanoprost acid + ester
Cornea
Latanoprost acid
Aqueous humour
FP receptor
c-fos
MMP
Ciliary muscle
Collagen  collagen fragments
Uveoscleral flow
Courtesy of Weinreb
OH
Latanoprost
COOCH (CH3)2
OH
OH
OH
Bimatoprost
Amide group
CONHCH2CH
OH
OH
Latanoprost
HO
COO-iPr
HO
HO
OH
Travoprost
COO-iPr
O
HO
OH
CF3
Flouride group
Study Design
•
Recruit subjects with POAG, PXE, PG or OAOH
•
Perform washout
•
Determine eligibility
•
Baseline diurnal curve
•
Randomize to the three treatment groups
• latanoprost 0.005%
• Bimatoprost 0.03%
• Travoprost 0.004%

Medication instilled daily at 8 PM
1. Parrish RK et al. Am J Ophthalmol. In press.
Unadjusted Mean IOP Levels by Treatment and
Measurement Time at Baseline and Week 12
Intent-to-Treat Population
Latanoprost
Mean IOP ± SEM (mm Hg)
26
Bimatoprost
25
24
23
Baseline
22
21
20
19
18
17
16
Travoprost
Week 12
15
8:00 AM
12 Noon
4:00 PM
Measurement Times
8:00 PM
IOP & IOP Change (mm Hg)
Unadjusted Means
Week 12 IOP
Latanoprost Bimatoprost Travoprost
(n=136)
IOP Change: Baseline to Week 12
Latanoprost Bimatoprost Travoprost
(n=136)
(n=138)
(n=136)
(n=136)
(n=138)
-8.70
-7.92
8 AM
17.09
17.03
17.59
-8.65
Noon
16.49
16.19
16.84
-7.17
-7.60
-6.78
4 PM
16.72
15.98
16.44
-6.23
-6.84
-6.30
8 PM
16.30
15.80
16.10
-5.91
-6.52
-5.72
Diurnal
16.71
16.35
16.81
-7.00
-7.33
-6.72
-0.05
-0.33
Adapted from Parrish RK et al. Am J Ophthalmol., 2003:135:688-703
Distributions of Reductions From Baseline to
Week 12 in 8 AM and Diurnal
Mean IOP Levels by Treatment
Intent-to-Treat Population
Mean IOP Change (mm Hg)
10
*
5
*
**
*
0
*
*
*
*
*
*
*
-5
-10
-15
-20
*
*
*
*
*
*
*
*
-25
*
*
*
*
*
*
*
-30
Latanoprost Bimatoprost
8 AM
Travoprost
Latanoprost
Bimatoprost
Diurnal
Travoprost
Percent of Patients Receiving
IOP-Reducing Medication at Screening
Intent-to-Treat Population
60
50
Before randomization to:
Latanoprost (n=136)
Patients (%)
Bimatoprost (n=137)
40
Travoprost (n=138)
30
20
10
0
Ocular Hypotensive Medications at Screening
Mean IOP at Screening by IOP-Reducing Medication
Mean IOP (mm Hg)
Intent-to-Treat Population
26
25
24
23
22
21
20
19
18
17
16
15
Latanoprost (n=136)
Bimatoprost (n=137)
Travoprost (n=138)
Ocular Hypotensive Medications at Screening
Distributions of Reductions From Baseline to Week 12
in 8 AM Mean IOP Levels by Treatment and
Prostaglandin Therapy at Screening
Intent-to-Treat Population; Post Hoc Analysis
Mean IOP Change (mm Hg)
10
5
Latanoprost
0
Bimatoprost
Travoprost
*
*
*
*
-5
-10
-15
-20
-25
-30
*
*
*
*
*
*
*
*
Hyperemia Grading Scale
Doctor’s Assessment
Adapted from Parrish RK et al. Am J Ophthalmol. 2003;145:
Patient’s Assessment of
Hyperemia
• “Have you or anyone else noticed any redness
in your eyes since the last visit?”
• If yes:
“To what extent does the redness bother you?”
– not at all
– small amount
– moderate amount
– a great deal
Mean Hyperemia Score by Treatment and Visit
Investigators’ Assessments
Mean Hyperemia Score ± SEM
1.0
0.9
Latanoprost
‡ P=.001,
Bimatoprost
Latanoprost vs Bimatoprost.
Travoprost
0.8
‡
‡
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Baseline
Week 2
Week 6
Visits
Week 12
Distributions of Reductions From Baseline to
Week 12 in 8 AM Mean IOP Levels by Treatment
and Occurrence of Hyperemia
Intent-to-Treat Population; Post Hoc Analysis
Mean IOP Change (mm Hg)
10
Latanoprost
Bimatoprost
Travoprost
*
**
*
*
*
5
0
*
*
-5
-10
-15
-20
**
*
*
*
*
*
*
*
-25
-30
Hyperemia
No
Hyperemia
Hyperemia
No
Hyperemia
No
Hyperemia
Hyperemia
Patients’ Assessments of Hyperemia
All Randomized Patients
50
Latanoprost
Percent Reporting
Any Redness in Eye(s)
Bimatoprost
40
§ P<.01,
Latanoprost vs Bimatoprost.1
|| P<.03, Latanoprost vs Travoprost.1
Travoprost
30
§
20
§, ||
§, ||
10
0
Baseline
Week 2
Week 6
Visits
Week 12
Adapted from Parrish RK et al. Am J Ophthalmol. 2003;145
1. Data on file. Pharmacia & Upjohn Company, Kalamazoo, MI.
Summary of Efficacy Results1
• Mean IOP levels at baseline were not significantly
different
• Mean IOP levels at 8 AM at week 12 were not
significantly different
• Mean IOP levels at week 12 were not significantly
different at any time point
• Mean diurnal IOP levels at week 12 were not
significantly different
• No racial differences in response to treatments
were observed (exploratory analysis)
1. Parrish RK et al. Am J Ophthalmol. 2003;135:411-417.
Conclusions
At week 12
• IOP reduction from baseline was not significantly
different in patients treated with latanoprost,
bimatoprost, or travoprost
• All 3 agents were generally well tolerated
systemically
• Significantly fewer patients reported symptoms of
ocular hyperemia with latanoprost treatment
• Investigators reported ocular hyperemia in
significantly fewer patients treated with latanoprost
than with bimatoprost
IOP Reduction as Demonstrated
in Head-to-Head Trials of PG Analogs
XLT Study:
(XALATAN® [latanoprost ophthalmic solution], Lumigan, and
Travatan)—a multicenter, randomized, parallel-group, maskedevaluator trial in patients with open-angle glaucoma (OAG) or
ocular hypertension (OHT) and a baseline IOP of 23 mm Hg;
study drugs dosed once daily at 8 PM.
1Parrish
RK et al. Am J Ophthalmol. 2003;135:411-417 .
IOP Reduction as Demonstrated
in Head-to-Head Trials of PG Analogs
A phase III, 4-arm, randomized trial in patients
with OAG or OHT; travoprost and latanoprost
dosed once daily.
1Parrish
RK et al. Am J Ophthalmol. In press. 2Netland PA et al. Am J Ophthalmol. 2001;132:472-484.
IOP Reduction as Demonstrated
in Head-to-Head Trials of PG Analogs
A multicenter, randomized,
investigator-masked, parallelgroup study in patients with
glaucoma or OHT and a mean
baseline IOP of 25.7 mm Hg;
study drugs dosed once daily
in the evening.
1Parrish
RK et al. Am J Ophthalmol. 2003; 135;411-417. 2Netland PA et al. Am J Ophthalmol. 2001;132:472-484.
S et al. Advances in Therapy. 2001;18:110-121.
3Gandolfi
IOP Reduction as Demonstrated
in Head-to-Head Trials of PG Analogs
A multicenter,
randomized,
investigatormasked study
in patients with
OHT or POAG;
study drugs
dosed once
daily.
†P<.001.
1Parrish
RK et al. Am J Ophthalmol. 2003;135:411-417. . 2Netland PA et al. Am J Ophthalmol. 2001;132:472-484.
S et al. Advances in Therapy. 2001;18:110-121. 4Noecker RS et al. Am J Ophthalmol. 2003;135:55-63.
3Gandolfi
Mean Diurnal IOP Reductions
Latanoprost Phase III vs Noecker et al
Reduction of Diurnal IOP
UK
Scandinavia USA
(6 mos)
(6 mos)
(6 mos)
n=179
n=183
n=128
Japan Philippines Mexico
(3 mos) (3 mos)
(3 mos)
n=89
n=30
n=57
Korea
(3 mos)
n=38
China Noecker
(3 mos) (6 mos)
n=63
n=136
IOP Reduction (mm Hg)
Mean ± SEM
0
-2
-4
-5.4
-6
-6.7
-7.2
-8
-10
-8
-8.5
-8
-8.6
-10.5
-8.2
Responder Rates
Noecker
Xal
Parrish
Lum
Xal
Tra
Lum
> 15% 72% 89%
91.9% 91.3% 91.9%
>20% 62% 79%
86.8% 84.8%
at 8 AM at end study
87.5%
Achieving Target Pressures
•
•
•
•
•
•
•
•
•
13 mm Hg
14 mm Hg
15 mm Hg
16 mm Hg
17 mm Hg
18 mm Hg
19 mm Hg
20 mm Hg
21 mm Hg
Xalatan
Travatan
11%
19%
27%
40%
52%
65%
77%
84%
90%
12%
19%
26%
33%
46%
60%
72%
80%
83%
Lumigan
10% AGIS
18%
29%
43%
59% CIGTS
68%
77%
82%
90%
More Aggressive Medical Therapy

Advanced Glaucoma Intervention Study (AGIS)
supports a 35-50% IOP reduction

Collaborative Normal-Tension Glaucoma Study (CNTGS)
supports a 30% IOP reduction

Comparison of Initial Glaucoma Treatment Study (CIGTS)
supports a 35% IOP reduction and EMGT would seem to support
more aggressive control.
Ocular Hypertension Treatment Study (OHTS) supports a 20-30%
IOP reduction

IOP vs 5 Yr Risk of Progression
CIGTS
POAG
NTG
OHTS
60
40
20
CIGTS
0
10
12
14
16
18
20
22
24
26
28