Transcript Bad Prognosis?

ADVANCES IN GLAUCOMA
DETECTION
MICHAEL CHAGLASIAN, OD
JOE SOWKA, OD
PAUL C. AJAMIAN, OD MODERATOR
CASE AC
 53 year old
 Myopia, no sig. medical history
 No family history glaucoma
 GAT= 27 OD 25 OS
 Gonioscopy= Open to CB 3600 OU
CASE AC:
IOP 27 OD; 25 OS
VISUAL FIELDS
SPECTRAL DOMAIN COMPARISON
Typical
SD OCT
SD OCT
w/tracking &
Noise
Reduction
CIRRUS SD OCT
Glaucoma
Applications:
• RNFL
• Optic Disc
• Ganglion Cell Analysis
Retinal Application:
6
• Not Covered here
HOW TO “READ” A PRINTOUT
 FIRST!:
Signal Strength
- A KEY indicator of image quality
- Should be 7/10 or higher on Cirrus
- DO NOT interpret poor quality scan as “red” disease
 Well centered image
 No evidence of movement artifact
 Review Plots and Displays
- Thickness Map and Deviation Map
- Quadrant and Sector Plots
- TSNIT and Optic Nerve B-Scan Tomograms
GLAUCOMA – RNFL
THICKNESS ANALYSIS
 The RNFL thickness map shows
the patterns and thickness of the
nerve fiber layer within the 6mm x
6mm cube
GLAUCOMA – RNFL
THICKNESS ANALYSIS
 RNFL thickness is
displayed in
graphic format and
compared to agematched normative
data
OPTIC NERVE HEAD
CALCULATIONS

The disc edge is determined by the
termination of Bruch’s membrane. This
is validated in the literature. The rim
width around the circumference of the
optic disc is then determined by
measuring the amount of neuro-retinal
tissue in the optic nerve. This differs
from other methods that determine the
cup margin based on its intersection
with a plane at a fixed distance above
the disc.

In this method, the disc and rim area
measurements correspond to the
anatomy in the same plane as the optic
disc.
NORMATIVE DATA: GLAUCOMA
Average RNFL Thickness
Distribution of Normals:
RNFL Symmetry
Color coded indication of normative data
comparison for RNFL and ONH.
Rim Area
Disc Area
Average C/D Ratio
Vertical C/D Ratio
Cup Volume
The thickest 5% fall in the white area.
90% of measurements fall in the green
area.
The thinnest 5% fall in the yellow area or
below.
The thinnest 1% of fall in the red area.
Measurements in red are considered
outside normal limits.
ONH values will be shown in gray when
the disc area does not match with
normative data.
CIRRUS: GANGLION CELL ANALYSIS
The analysis contains:
 Data for both eyes (OU)
 Thickness Map –
- shows thickness measurements of the
GCL + IPL in the 6mm by
6mm cube and contains an
elliptical annulus centered about the
fovea.
 Deviation Maps –
- shows a comparison of GCL + IPL
-
thickness to normative data.
 Thickness table –
- shows average and minimum thickness
within the elliptical annulus.
MACULAR/GANGLION CELL
ANALYSIS FOR GLAUCOMA: KEY
POINTS
 Is a “complement” to traditional RNFL scans
 Has a large number of false positives.
 Should NOT be used as the sole basis of a
diagnosis for glaucoma.
 Not proven to make an earlier diagnosis.
14
IS ALL OF THIS GREAT AND
PERFECT??
What are practitioners' most common
misunderstandings of imaging technology?
“The thought that these devices can diagnose glaucoma in the
absence of corroborating clinical evidence is, in my opinion,
the most common (and potentially dangerous)
misunderstanding.
The limited normative databases against which scans are
compared can never cover the remarkably varied appearance
and structure of the optic nerve we encounter in normal
individuals.”
James Brandt, MD
RED DISEASE!
RED DISEASE
READ A PRINTOUT SUMMARY
 Image Quality
 Step by step to review most plots.
 RNFL and Optic Nerve
 Localized vs. Diffuse
 Normative Data
 Red Disease
18
BAD PROGNOSIS?
 78 YOWF
 Average IOP (1 yr x5); 22 mm OD, 20 mm OS
 CCT: 517 OD, 527 OS
 PXE material OU
 Gonio open OU with moderate pigment
BAD PROGNOSIS?
 PXE glaucoma diagnosed
Considerations:
- Mild field loss
- Older age
- Lower initial baseline IOP
- PXE
Can this patient be monitored or should she
be treated?
BAD PROGNOSIS?
 Pt answers the question- declines treatment
 Bad experience with treatment suggested by
doctors in past
- more afraid of treatment than glaucoma
- Wants to see change or other conclusive proof of need
for treatment.
However, everything says she will do poorly
 Peak IOP: 34 mm Hg OD, 37 mm Hg OS
ALL GLAUCOMA IS NOT CREATED EQUAL
 71 YOF
 Diagnosed POAG OU 2009- treated with Travatan
Z will good response (IOP drops to 18 from 28)
 CCT: 579, 583
 Transfers care for convenience
 Angles open- no evidence of secondary
glaucoma
ALL GLAUCOMA IS NOT CREATED EQUAL
 2012: 20/30 OD, 20/400 OS
 SLT OU x2
 Meds: Lumigan, Combigan, Azopt
 Hx: Used oral CAI 3x/day- hands and feet hurt too much to
continue
 Used pilocarpine- motion sickness
 IOP- 22 mm OD and 38 mm OS
ALL GLAUCOMA IS NOT CREATED EQUAL
 Visit 2/14
 Not seeing OS since 9/13
 20/50 OD, LP OS
 IOP 36 mm OD, 30 mm OS
 Now What?
 Declines surgery again and again
ALL GLAUCOMA IS NOT CREATED EQUAL
 N/S until 2/15
 Did request med refills throughout, however
 Using Combigan only- ran out of Azopt and Travatan
 20/60 OD, NLP OS
 IOP 46 mm OD and 72 mm OS
 Refill all meds
 Declines surgery again
ALL GLAUCOMA IS NOT CREATED EQUAL
 Visit 6/15
 Using meds regularly, but was confused when to use Travatan
so didn’t use it in past week
 Vision unchanged
 IOP: 40 mm OD and 53 mm OS
 New views on surgery
CLINICAL PEARL
 You can only call a glaucoma patient “well
controlled” in retrospect
 Some patients progress slowly without treatment and
some progress rapidly, even with treatment
- You don’t know who is who until you follow up over time
CASE EG
 67 yo, AA male, Retired school teacher
 Good health, no medications
 + Family History of glaucoma
 OHTN/Early Glaucoma
 CCT= 567, 571
 Pre- Tx IOP ~ 30 mmHg OD, OS
 With PGA:
- Always 20-23 mmHg x 5+yrs
- Good Compliance
CAN YOU SEE THE CHANGE?
TWO YEARS LATER
FORUM COMBINED REPORT
CASE EG DISCUSSION
 Is this progression?
 Other things you’d like to see/do?
 Options for adjunctive treatment?
ASYMMETRIC PROGRESSION?
 76 YOWM- 2008; now 83; US citizen, lives/works
Brazil
 BPH, hypercholesteremia, aortic stenosis
- Crestor, Flomax, Levitra
 20/20 OD, OS
 Peak IOP 25 mm OD, 20 mm OS
 CCT 618 OU
 PERRL (-) RAPD; gonio/SLE normal
 Dx’ed POAG OS; OHTN OD vs early POAG
 Travatan OU
- Occasionally used DuoTrav
 15-16 mm Hg OU
ASYMMETRIC PROGRESSION?
 Treated IOP mid teens
 Marked field progression OS only
- Meds changed throughout
 BP 114/70; 46 BPM
 Travatan Z/ Simbrinza
- IOP 12 mm Hg OU
 Why asymmetric (rapid) marked progression
OS?
 What else to look for?
 Next step?
CASE CM
38 YO
GAT= 22 OD 25 OS
WAS ON XALATAN IN PAST
? OF SIDE EFFECTS AND/OR POOR RESPONSE
VISUAL FIELDS
COMBINED REPORT
CASE LH
57 YO, W, F
-7.50 MYOPIA
GAT: 19-23 / 18-23
CCT= 562, 571
VISUAL FIELDS
COMBINED REPORT
GPA SUMMARY
NANNY NTG
 42 YOHF referred for glaucoma evaluation by
colleague/ retinal surgeon
 Verbal report- IOP low-mid teens at diagnosis
 Given travoprost- no IOP effect- stopped




Inquires about surgery and neuroimaging
VA 20/ 20 OD, OS; PERRL RAPD OS
CCT 523 OD, 526 OS
TA:
 OD: 13, 12, 16, 16
 OS: 14, 14, 14, 14
 Gonio: posterior TM OU- no abnormalities
NANNY NTG
 How do you approach NTG evaluation?
 What do you look for?
 What is appropriate treatment?
 Target IOP?
NANNY NTG
 No med hx: Denies blood loss, syncope, inversion
 BP: 115/80; BMI 25
 Poor medical effect of multiple medications
- Travoprost, cosopt, combigan, dorzolamide
 Start bimatoprost 0.01%
- IOP 09 mm OU
• Success?
GLAUCOMA EPIDEMIOLOGY AND
TREATMENT
Current Medical Treatments for OAG
Aqueous Production
-blocker
CAI
2-agonist
 Aqueous Outflow
Conventional
Unconventional
Cholinergic agonist
Docosanoid?
Prostaglandin
analog
2-agonist
Quadruple-Action
PG324 (ROCK-NET Inhibitor/latanoprost)- Roclatan
Fixed Combination of AR-13324 with Latanoprost
4 Identified
IOP-Lowering Mechanisms
 ROCK inhibition relaxes TM1,
increases outflow1,2
 NET inhibition reduces fluid
production2
 ROCK inhibition
lowers EVP3
 PGA receptor activation
increases uveoscleral
outflow4
1.Wang SK, Chang RT. An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin Ophthal 2014;8:883-890.
2.Wang RF, Williamson JE, Kopczynski C, Serle JB. Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous
humor dynamics in normotensive monkey eyes. J Glaucoma 2015. 24(1):51-4.
3.Kiel JW, Kopczynski C. Effect of AR-13324 on episcleral venous pressure (EVP) in Dutch Belted rabbits. ARVO 2014. Abstract 2900
4.Latanoprost prescribing information
46
RHO KINASE INHIBITION
New Development in IOP Reduction
Rho-GTP
Rho activation increases contractility of
TM cells
Rho Kinases
(ROCK1, 2)
• Induces myosin light chain phosphorylation
• Results in formation of actin stress fibers and
focal adhesions – increased contractility
• Reduces outflow of aqueous humor
Rho kinase inhibition relaxes TM cells
• Reduces actin stress fibers/focal adhesions
• Increases outflow of aqueous humor
Rho kinase inhibition may also:
• Increase ocular blood flow
MLCP-PPase
MLC
MLC-P
MLCK
LIMK1,2
Actomyosin
Contractility
Actin Stress Fibers
Assembly/Stability
• Increase retinal ganglion cell survival
Uehata M, et al. Nature 1997;389:990-994
Hirata A, et al. Graefes Arch Clin Exp Ophthalmol. 2008;246(1):51-59
Wang SK, Chang RT. Clin Ophthalmol 2014;8:883-890
Focal Adhesion
Assembly/Stability
AR-13324 MOA: AFFECTING TM IN
PATIENTS WITH GLAUCOMA
+ AR-13324
Cellular Stress
 Aging
 Oxidation
Healthy TM
Reduced
Fibrosis, Stiffness
Contraction
Less Cellular Stress
Increased Aqueous
Perfusion Area
More Nutrients,
Antioxidants
Reduced IOP
Preserve Vision
REDUCING FIBROSIS, INCREASING TRABECULAR OUTFLOW COULD
STOP DEGENERATION OF OUTFLOW TISSUES IN POAG
Sources: Wang SK, Chang RT. An emerging treatment
option for glaucoma: Rho kinase inhibitors. Clin
AR-13324 (ROCK-NET INHIBITOR)
TRIPLE-ACTION
3 Identified IOP-Lowering Mechanisms
 ROCK inhibition relaxes TM1,
increases outflow1,2
 NET inhibition reduces fluid
production2
 ROCK inhibition lowers
Episcleral Venous
Pressure (EVP)3
1.
Wang SK, Chang RT. An emerging treatment
option for glaucoma: Rho kinase inhibitors. Clin
AR-13324 (ROCK-NET INHIBITOR):
PHASE 2B IOP LOWERING RESULTS
Mean Diurnal IOP – Entry IOP 22-36 mmHg (n=221)
 Once-daily PM dosing of 0.02% AR-13324 is effective
– IOP -5.7 and -6.2 mmHg on D28 and D14
 AR-13324 efficacy results within ~1 mmHg of latanoprost
 Favorable tolerability profile with no systemic side effects
Source: Double-masked, Randomized, Dose Response
Study of AR-13324 versus Latanoprost in Patients
AR-13324 (ROCK-NET INHIBITOR)
REGISTRATION TRIAL DESIGN
“Rocket 1”
90-Day Efficacy
Registration Trial
“Rocket 2”
One Year Safety
(3 Mo. Interim
Efficacy)
Registration Trial
“Rocket 3”
One Year Safety
Registration Trial
Canada
 AR-13324 0.02% QD
~200 patients
 Timolol BID
~200 patients
 AR-13324 0.02% QD
~230 patients
 AR-13324 0.02% BID*
~230 patients
 Timolol BID
~230 patients
 AR-13324 0.02% QD
~90 patients
 AR-13324 0.02% BID
~90 patients
 Timolol BID
~60 patients
* PGAs have been shown to be less effective when
dosed BID
AR-13324 (ROCKET 1) EFFICACY
RESULTS AT DIFFERENT
BASELINE IOPS
Baseline IOP (mmHg)
Non-inferiority
Numerical Superiority
<27*
Did not meet
Met 2 time points
<26***
Met
Met 4 time points
<25***
Met
Met 7 time points
<24**
Met
Met All 9 time points
<23***
Met
Met All 9 time points
* Primary endpoint
** Pre-specified secondary endpoint
*** Post-Hoc Analysis
AR-13324 PATH FORWARD:
ROCKET 2 STUDY
Rocket 2 is a 12-month Phase 3 study of AR-13324 vs. Timolol
The patient group to be used for Rocket 2 primary endpoint analysis
was recently changed with FDA agreement
Primary endpoint analysis will include only patients with a baseline
IOP above 20 mmHg and below 25 mmHg
Statistical analysis confirmed Rocket 2 adequately powered for this
subgroup analysis with no additional patient enrollment necessary
Rocket 2 database not yet locked; patients still being treated
3-month efficacy read-out expected end of Q3 2015
RHOPRESSA
TM
(AR-13324 0.02%)
 Was seen as less effective than latanoprost
by approximately 1 mmHg in patients with
elevated IOP
 RhopressaTM did not meet the primary
efficacy endpoint of demonstrating noninferiority to twice-daily dosing of timolol.
RhopressaTM also showed a slight loss of
efficacy over time.
 Seems to work best at modest IOP baseline
Quadruple-Action
PG324 (ROCK-NET Inhibitor/latanoprost)- Roclatan
Fixed Combination of AR-13324 with Latanoprost
4 Identified
IOP-Lowering Mechanisms
 ROCK inhibition relaxes TM1,
increases outflow1,2
 NET inhibition reduces fluid
production2
 ROCK inhibition
lowers EVP3
 PGA receptor activation
increases uveoscleral
outflow4
1.Wang SK, Chang RT. An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin Ophthal 2014;8:883-890.
2.Wang RF, Williamson JE, Kopczynski C, Serle JB. Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous
humor dynamics in normotensive monkey eyes. J Glaucoma 2015. 24(1):51-4.
3.Kiel JW, Kopczynski C. Effect of AR-13324 on episcleral venous pressure (EVP) in Dutch Belted rabbits. ARVO 2014. Abstract 2900
4.Latanoprost prescribing information
55
ROCLATANTM
 RoclatanTM is a fixed combination agent
composed of RhopressaTM and latanoprost
0.005%. With the addition of latanoprost to
the mix, RoclatinTM claims to possess
“quadruple-action”, adding increased
uveoscleral outflow to the mechanisms
reported by RhopressaTM alone.
 RoclatanTM achieving statistical superiority
relative to both latanoprost and RhopressaTM,
providing additional IOP lowering of 1.9 and
2.6 mm Hg, respectively
PG324 ACHIEVED STATISTICAL SUPERIORITY OVER
INDIVIDUAL COMPONENTS AT ALL TIME POINTS
(P<0.001)
Mean IOP at Each Time Point (Primary Efficacy Measure)
PG324 Phase 2b, Intent to Treat
Source: Bacharach J, Levy B, Ramirez N, Kopczynski
VESNEO™ (LATANOPROST BUNOD)
 Nitric oxide-donating prostaglandin F2-alpha
analog licensed by Nicox to Bausch + Lomb
and currently in phase 3 clinical
development.
 In Phase 3 studies, Vesneo™ reached its
desired primary endpoint of non-inferiority to
timolol maleate 0.5%, actually showing
superiority to the beta blocker.
 Vesneo ™ showed a reduction in mean IOP of
7.5 to 9.1 mmHg from baseline between 2 and
12 weeks through Phase 3 studies
VESNEO™ (LATANOPROST BUNOD)
 VOYAGER Study, it was seen that latanoprost
bunod 0.024% dosed once daily gave
significantly greater IOP lowering and
comparable side effects relative to
latanoprost 0.005%. The most common side
effect was hyperemia, which was well
tolerated.
 Bausch + Lomb expects to submit a new drug
application to the FDA and hopes to launch
VesneoTM in the US in the first half of 2016
TRABODENOSONTM
 Inotek Pharmaceutical’s compound is
considered to be a first-in-class selective
adenosine mimetic whose action appears to
be increased trabecular aqueous outflow.
 Stimulates adenosine receptors, increasing
metabolic activity in the trabecular
meshwork. The increased metabolic activity
upregulates proteases that digest and
remove accumulated proteins which hinder
trabecular aqueous outflow
TRABODENOSONTM
 TrabodenosonTM -long duration of action,
making QD dosing possible
 Approximates the IOP lowering efficacy of
prostaglandin analogs.
 It also appears to have an additive effect to
other second-line glaucoma medications
such as beta blockers and carbonic
anhydrase inhibitors
TAPTIQOM®
 Santen Pharmaceuticals (Osaka, Japan), may
attempt to bring to the US market a fixed
combination prostaglandin analog/ beta
blocker. The agent, Taptiqom® combines
tafluprost 0.0015% with timolol 0.5% in a
preservative-free, unit-dose vial.
TAPTIQOM®
 A 6-month, prospective, randomized, doublemasked, parallel group, multicenter phase III
study comparing the fixed combination agent
to concomitant use of both components.
 It was seen that the tafluprost/timolol fixed
combination showed IOP reductions that
were both statistically and clinically
significant and non-inferior to those of the
concomitant usage of the individual
components.
- In fact, the fixed combination agent outperformed the
concomitant use of both products.
Holló G, Hommer A, Antón López A, Ropo A. Efficacy, safety, and tolerability of preservative-free fixed combination of
tafluprost 0.0015%/timolol 0.5% versus concomitant use of the ingredients. J Ocul Pharmacol Ther. 2014;30(6):468-75.
TAPTIQOM®
 Similarly, in a study involving exfoliative
glaucoma patients, the fixed combination
agent performed similarly to the two agents
used concomitantly.
Holló G, Ropo A. Intraocular pressure decrease with preservative-free fixed
and unfixed combination of tafluprost and timolol in pseudoexfoliative
glaucoma. Curr Med Res Opin. 2015;31(1):13-6.
CASE ML
47 YRS OLD
GAT = ~ 20-21 OD AND OS
ASYMMETRIC CUPPING
CCT= 525 OD OS
CORNEAL HYSTERESIS= 8.1