Lessons from the Ocular Hypertension Treatment Study (OHTS) - PowerPoint

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					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                        Inhibition of aqueous production
   inhibitors                                by the ciliary epithelium

   Prostaglandin F2                         Increased uveoscleral outflow
   derivatives


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                      Latanoprost              Timolol
 end of treatment                      (n=398)                (n=318)   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 <0.001 (Pearson chi-square test) latanoprost vs timolol
**P <0.002 (Pearson chi-square test) latanoprost vs timolol

Pharmacia. Data on file.
      Diurnal IOP Reduction at 3 Months

             Change in IOP From Baseline (mm Hg)                                Timolol +
                                                        Latanoprost            Dorzolamide
                                                           (n=85)                (n=90)
                                                   0
                                                   -1
                         (Mean ± SEM)




                                                   -2

                                                   -3

                                                   -4

                                                   -5

                                                   -6                 P=0.79

                                                        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
                Week 6            Week 12
      0

     -5

    -10

    -15
                                                        Latanoprost
    -20
                    20%                 20%              Timolol
    -25

    -30
                                30%
    -35       33%
                                Chew, on behalf of the EXACT Study Group (2001)
      Latanoprost vs Timolol in CACG
ITT population
% patients
                                                    P<.002
80                                                                  Latanoprost
70                                                                  Timolol
                          P<.001
60

50

40
     P<.001
30

20

10

 0
      15     16   17     18   19         20      21       >21
                           IOP (mm Hg)
                                   Chew, on behalf of the EXACT Study Group (2001)
                                                Latanoprost Efficacy in
                                                Pigmentary Glaucoma
                                                 Diurnal IOP reduction
                                            8
      Change in IOP From Baseline (mm Hg)




                                                 P<0.001        P<0.001

                                            7

                                            6
                  (Mean ± SEM)




                                            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
                        5
                                                                  *The ratio between the
        Relative Risk




                        4                                          incidence of a disease
                                                                   symptom among
                                                                   individuals
                        3
                                                                   with a given risk factor to
                                                                   the incidence among
                        2
                                                                   those without it.

                        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
            23
                                                                          e
                                                                        Dorzolamide
            21                                                               tid
            19
                                                                       Timolol bid
            17                                                             Latanoprost
            15                                                                 qd
            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    OH
                                 Double bond    Phenyl
Stjernschantz, IOVS, 2001                       substitution
                                 saturation
  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
      OH



HO
     Travoprost
                  COO-iPr

           O

HO
      OH                    Flouride group
                     CF3
          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
                         26                                      Bimatoprost
                         25                                      Travoprost
Mean IOP ± SEM (mm Hg)




                                                     Baseline
                         24
                         23
                         22
                         21
                         20
                         19
                                                      Week 12
                         18
                         17
                         16
                         15
                              8:00 AM   12 Noon        4:00 PM     8:00 PM
                                            Measurement Times
               IOP & IOP Change (mm Hg)
                           Unadjusted Means

                     Week 12 IOP                    IOP Change: Baseline to Week 12
          Latanoprost Bimatoprost Travoprost       Latanoprost Bimatoprost Travoprost
           (n=136)      (n=136)     (n=138)            (n=136)             (n=136)             (n=138)
8 AM         17.09        17.03       17.59               -8.65       -0.05    -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       -0.33    -7.33               -6.72




                                              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
                          10
                                                                                                       *
                           5
Mean IOP Change (mm Hg)




                                                              *
                                                 *            *                           *
                                                 *
                                                 *            *                                        *
                           0                     *                          *             *

                           -5

                          -10
                                                                                                       *
                          -15                    *            *             *             *            *
                                    *            *            *                           *            *
                          -20       *            *
                                    *
                          -25                                               *

                          -30
                                Latanoprost Bimatoprost   Travoprost   Latanoprost   Bimatoprost   Travoprost

                                               8 AM                                  Diurnal
                        Percent of Patients Receiving
                    IOP-Reducing Medication at Screening
                           Intent-to-Treat Population
               60                            Before randomization to:
                                                Latanoprost (n=136)
               50
                                                Bimatoprost (n=137)
Patients (%)




               40                               Travoprost (n=138)

               30

               20

               10

               0




                        Ocular Hypotensive Medications at Screening
                    Mean IOP at Screening by IOP-Reducing Medication
                                 Intent-to-Treat Population

                   26        Latanoprost (n=136)
                   25        Bimatoprost (n=137)
                   24        Travoprost (n=138)
Mean IOP (mm Hg)




                   23
                   22
                   21
                   20
                   19
                   18
                   17
                   16
                   15




                              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
                          10
Mean IOP Change (mm Hg)




                           5        Latanoprost       Bimatoprost      Travoprost
                                                                       *
                           0                          *                *
                                                                       *
                           -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


                                                                                          Latanoprost
                             1.0
                                       ‡ P=.001,   Latanoprost vs Bimatoprost.            Bimatoprost
Mean Hyperemia Score ± SEM




                             0.9
                                                                                          Travoprost
                             0.8
                                                              ‡
                                                                                                  ‡
                             0.7
                             0.6
                             0.5
                             0.4
                             0.3
                             0.2
                             0.1
                              0
                                   Baseline                Week 2                Week 6       Week 12
                                                                    Visits
                            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

                          10
                                   Latanoprost             Bimatoprost           Travoprost
Mean IOP Change (mm Hg)




                           5
                                                                                  *
                                                           *                      *
                           0                               *           *          *
                                                           *
                                                                       *
                           -5

                          -10

                          -15
                                                           *
                                                           *                      *
                                    *                      *                      *
                          -20
                                    *                                  *
                          -25                   *

                          -30
                                Hyperemia      No       Hyperemia      No     Hyperemia    No
                                            Hyperemia               Hyperemia           Hyperemia
                             Patients’ Assessments of Hyperemia
                                          All Randomized Patients
                        50                                                                       Latanoprost
                                                                                                 Bimatoprost
                               § P<.01,  Latanoprost vs Bimatoprost.1
                        40                                                                       Travoprost
Any Redness in Eye(s)




                               || P<.03, Latanoprost vs Travoprost.1
  Percent Reporting




                        30

                                                                               §
                        20                            §, ||                                                 §, ||




                        10


                         0
                               Baseline           Week 2                 Week 6                       Week 12
                                                              Visits
                                                                       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, 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. 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, 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; 135;411-417. 2Netland PA et al. Am J Ophthalmol. 2001;132:472-484.
   3Gandolfi   S et al. Advances in Therapy. 2001;18:110-121.
   IOP Reduction as Demonstrated
in Head-to-Head Trials of PG Analogs




                                                                                                   A multicenter,
                                                                                                   randomized,
                                                                                                   investigator-
                                                                                                   masked 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.
   3Gandolfi   S et al. Advances in Therapy. 2001;18:110-121. 4Noecker RS et al. Am J Ophthalmol. 2003;135:55-63.
                              Mean Diurnal IOP Reductions
                         Latanoprost Phase III vs Noecker et al

                                                          Reduction of Diurnal IOP

                                 UK   Scandinavia USA       Japan Philippines Mexico     Korea     China Noecker
                              (6 mos)   (6 mos)  (6 mos)   (3 mos) (3 mos)    (3 mos)   (3 mos)   (3 mos) (6 mos)
                               n=179    n=183     n=128      n=89    n=30      n=57      n=38      n=63    n=136
                         0
IOP Reduction (mm Hg)




                         -2
     Mean ± SEM




                         -4
                                                                                                           -5.4

                         -6
                                                  -6.7
                                                             -7.2
                                         -8                                               -8      -8.2
                         -8    -8.5                                   -8.6

                                                                               -10.5
                        -10
                  Responder Rates



  Noecker                                   Parrish
   Xal      Lum                  Xal          Tra     Lum
> 15% 72% 89%                   91.9% 91.3%           91.9%
>20% 62% 79%                    86.8% 84.8% 87.5%


                     at 8 AM at end study
         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%
    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

 0                                                      CIGTS
     10   12   14   16   18   20   22   24    26   28

				
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