Evidence-Based Glaucoma Therapy

1
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
2
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.
3
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

4
Natures Experiment-EpidemiologyThe lower the
better?
Prevalence of POAG in Relation to Screening IOP

• There is a dose-response relationship between
  the IOP and the risk of VF damage
• In the general population Baltimore Eye Study
  Data
• Every 3 points changes prevalence by about 50

Sommer A, et al. Arch Ophthalmol.
19911091090-1095.
5
Meta-Analysis of Multiple Trials (UK, Scandinavia
and USA)
Percentage of patients reaching a specific target
IOP

• Diurnal IOP at Latanoprost Timolol end of
  treatment (n398) (n318) Odds ratio

• ?15 mm Hg 27 14 2.2
• ?16 mm Hg 39 26 1.8
• ?17 mm Hg 56 38 2.0
• ?18 mm Hg 70 55 1.9
• ?19 mm Hg 83 72 1.9
• ?20 mm Hg 89 81 1.9

P lt0.001 (Pearson chi-square test) latanoprost
vs timolol P lt0.002 (Pearson chi-square test)
latanoprost vs timolol Pharmacia. Data on file.
6
Diurnal IOP Reduction at 3 Months
Timolol Dorzolamide (n90)
Latanoprost (n85)
0
-1
-2
Change in IOP From Baseline (mm Hg) (Mean SEM)
-3
-4
-5
P0.79
-6
Least Square Means (ANCOVA)
Emmerich KH. Graefes Arch Clin Exp Ophthalmol.
200023819-23. Emmerich KH, et al. AAO, New
Orleans, USA, 1998.
7
Latanoprost vs Timolol in CACG

• ITT population

decrease in IOP from baseline
Week 6
Week 12
0
-5
-10
-15
Latanoprost
-20
20
20
Timolol
-25
-30
30
33
-35
Chew, on behalf of the EXACT Study Group (2001)
8
Latanoprost vs Timolol in CACG

• ITT population

patients
Plt.002
80
Latanoprost
Timolol
70
Plt.001
60
50
40
Plt.001
30
20
10
0
?15
?16
?17
?18
?19
?20
?21
gt21
IOP (mm Hg)
Chew, on behalf of the EXACT Study Group (2001)
9
Latanoprost Efficacy in Pigmentary Glaucoma

• Diurnal IOP reduction

• Plt0.001

• Plt0.001

Change in IOP From Baseline (mm Hg) (Mean SEM)

• 6 months

• 12 months

• Mastropasqua L, et al. Ophthalmology,
  1999106550-555.

10
Diurnal IOP Range and Disease Progression
Relative risk of disease progression within 5
years
5.76
The ratio between the incidence of a disease
symptom among individuals with a given risk
factor to the incidence among those without it.
Relative Risk
1.00
Diurnal IOP Range 3.1 mm Hg
Diurnal IOP Range 5.4 mm Hg
Asrani S, et al. J Glaucoma. 20009134-142.
11
Latanoprost qd vs Dorzolamide tid and Timolol
bid Over 24 Hours
Circadian control of IOP
Baseline
Dorzolamide tid
Timolol bid
IOP (mm Hg)
Latanoprost qd
Time (Hours)
Orzalesi N, et al. Invest Ophthalmol Vis Sci.
2000412566-2573.
12
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
135688-703
13
OH
COOH
PGF2?
CH3
OH
OH
10 years
Esterification
OH
COOCH(CH3)2
LATANOPROST
OH
OH
Phenyl substitution
Double bond saturation
Stjernschantz, IOVS, 2001
14
Latanoprost hypothesized mechanism of action
Latanoprost
Latanoprost acid ester
Cornea
Latanoprost acid
Aqueous humour
FP receptor
c-fos
Ciliary muscle
MMP
Collagen collagen fragments
Uveoscleral flow
Courtesy of Weinreb
15

Latanoprost





Bimatoprost
Amide group


16
Latanoprost
Travoprost
Flouride group
17
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.

18
Unadjusted 8 AM Mean IOP Levels by Treatment and
Visit Intent-to-Treat Population
26
Latanoprost Bimatoprost Travoprost
25
24
23
22
21
Mean IOP SEM (mm Hg)
20
19
18

17
16
15
Baseline
Week 2
Week 6
Week 12
Visits
19
Unadjusted Mean IOP Levels by Treatment and
Measurement Time at Baseline and Week 12
Intent-to-Treat Population
26
25
Baseline
24
23
22
21
Mean IOP SEM (mm Hg)
20
19
Week 12
18
17
16
15
800 AM
12 Noon
400 PM
800 PM
Measurement Times
20
IOP IOP Change (mm Hg)
Unadjusted Means
Week 12 IOP
IOP Change Baseline to Week 12
Latanoprost
Bimatoprost
Travoprost
Latanoprost
Bimatoprost
Travoprost
(n136)
(n136)
(n138)
(n136)
(n136)
(n138)
-0.05
8 AM
17.09
17.03
17.59
-8.65
-8.70
-7.92
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
-0.33
Adapted from Parrish RK et al. Am J Ophthalmol.,
2003135688-703
21
Distributions of Reductions From Baseline to Week
12 in 8 AM and Diurnal Mean IOP Levels by
Treatment Intent-to-Treat Population
10

5









0


-5
-10
Mean IOP Change (mm Hg)

-15












-20

-25

-30
Latanoprost
Bimatoprost
Travoprost
Latanoprost
Bimatoprost
Travoprost
8 AM
Diurnal
22
Percent of Patients Receiving IOP-Reducing
Medication at Screening Intent-to-Treat
Population
Before randomization to
Patients ()
Prostaglandin analogs (n205)
Carbonic anhydrase inhibitors (n142)
Adrenergic receptor agonists (n55)
Combination (n14)
Masked investigational medication (n10)
Cholinergic agonists (n4)
?-adrenergic receptor antagonists (?-blockers)
(n116)
Ocular Hypotensive Medications at Screening
23
Mean IOP at Screening by IOP-Reducing Medication
Intent-to-Treat Population
Mean IOP (mm Hg)
Prostaglandin analogs (n205)
Combination (n14)
Masked investigational medication (n10)
Cholinergic agonists (n4)
Carbonic anhydrase inhibitors (n142)
Adrenergic receptor agonists (n55)
?-adrenergic receptor antagonists (?-blockers)
(n116)
Ocular Hypotensive Medications at Screening
24
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
10
25
Hyperemia Grading Scale1

• Based on standard photographs provided
• Four-point scale
• 0 none
• 1 mild
• 2 moderate
• 3 severe
• Valid scores 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0

26
Hyperemia Grading ScaleDoctors Assessment
Adapted from Parrish RK et al. Am J Ophthalmol.
2003145
27
Patients 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

28
Mean Hyperemia Score by Treatment and Visit
Investigators Assessments
1.0
P.001, Latanoprost vs Bimatoprost.
0.9
0.8

0.7

0.6
Mean Hyperemia Score SEM
0.5
0.4
0.3
0.2
0.1
0
Baseline
Week 2
Week 6
Week 12
Visits
29
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
30
Patients Assessments of HyperemiaAll Randomized
Patients
Latanoprost Bimatoprost Travoprost
Plt.01, Latanoprost vs Bimatoprost.1 Plt.03,
Latanoprost vs Travoprost.1
Percent Reporting Any Redness in Eye(s)

,
,
Visits
Adapted from Parrish RK et al. Am J Ophthalmol.
2003145 1. Data on file. Pharmacia Upjohn
Company, Kalamazoo, MI.
31
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.
  2003135411-417.

32
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

33
IOP Reduction as Demonstratedin Head-to-Head
Trials of PG Analogs
XLT Study(XALATAN latanoprost ophthalmic
solution, Lumigan, and Travatan)a multicenter,
randomized, parallel-group, masked-evaluator
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.
2003135411-417 .
34
IOP Reduction as Demonstratedin 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.
2001132472-484.
35
IOP Reduction as Demonstratedin Head-to-Head
Trials of PG Analogs
A multicenter, randomized, investigator-masked,
parallel-group 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
135411-417. 2Netland PA et al. Am J
Ophthalmol. 2001132472-484. 3Gandolfi S et al.
Advances in Therapy. 200118110-121.
36
IOP Reduction as Demonstratedin Head-to-Head
Trials of PG Analogs
A multicenter, randomized, investigator-masked
study in patients with OHT or POAG study drugs
dosed once daily. Plt.001.
1Parrish RK et al. Am J Ophthalmol.
2003135411-417. . 2Netland PA et al. Am J
Ophthalmol. 2001132472-484. 3Gandolfi S et al.
Advances in Therapy. 200118110-121. 4Noecker RS
et al. Am J Ophthalmol. 200313555-63.
37
Mean Diurnal IOP ReductionsLatanoprost Phase III
vs Noecker et al
38
Responder Rates

• Noecker
  Parrish
• Xal Lum
  Xal Tra Lum
• gt 15 72 89 91.9
  91.3 91.9
• gt20 62 79 86.8
  84.8 87.5
• 
  at 8 AM at end study

39
Achieving Target Pressures

• Xalatan
  Travatan Lumigan
• 13 mm Hg 11 12
  10 AGIS
• 14 mm Hg 19 19
  18
• 15 mm Hg 27 26
  29
• 16 mm Hg 40 33
  43
• 17 mm Hg 52 46
  59 CIGTS
• 18 mm Hg 65 60
  68
• 19 mm Hg 77 72
  77
• 20 mm Hg 84 80
  82
• 21 mm Hg 90 83
  90

40
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

41
IOP vs 5 Yr Risk of Progression