This document summarizes key information about managing retinal disorders like age-related macular degeneration (AMD). It discusses the evolution of treatment regimens for AMD from monthly injections to treat-and-extend approaches. It also reviews important clinical trials on AMD treatments and imaging techniques like OCT and OCT-A. Overall, the document emphasizes that AMD requires long-term, individualized management to optimize outcomes while minimizing treatment burden.

1. Managing Retinal Disorders:
UPDATES FOR THE N0n - RETINA SPECIALIST
Focus On AMD

2.  Some follow the treatment protocols specified in the
trials
 Others have adjusted their regimens to achieve
similar results with fewer injections
Two Types of practitioners:
Points to understand

3.  Maintaining optimal visual acuity over the long
term
 Being sensitive to the often-burdensome
treatment schedules
 Dosing methodologies
 Treatment outcomes
 Individualizing Strategies
NAMD management:
Challenges

4. Evolution of strategies
 Monthly
 PRN
 TAE
 ????
 Monthly
 Bimonthly
 Quarterly dosing
(continuous-fixed)
 PRN (discontinuous-
variable)
 Treat-and-extend
(continuous-variable)

5. AMD Trails
 ANCHOR
 ATLAS
 HARBOUR
 HORIZON
 HAWK
 HARRIER
 MARINA
 PRONTO
 SEVEN UP
 VIEW

6.  CATT:
 Comparison of Age-related Macular Degeneration Treatments
Trials
 IVAN:
 Inhibit VEGF in Age- related Choroidal Neovascularisation
 NOT AS GOOD AS PRONTO EXPECTED TO DO
 LUCAS:
 Lucentis Compared to Avastin Stud: show that a treat-and-
extend approach works as well as we would expect with a fixed
monthly dosing interval
 ALTAIR:
 JAPAN; post hoc analysis of the VIEW 1 and VIEW 2 studies of
aflibercept (PCV)
More Clinical Trails

7. More…....
 MARINA :
 Minimally Classic/Occult
Trial of the Anti-VEGF
Antibody Ranibizumab
in the Treatment of
Neovascular AMD
 ANCHOR:
 Anti-VEGF Antibody for
the Treatment of
Predominantly Classic
Choroidal
Neovascularization in
AMD

8.  The indirect and direct cost of treating patients too
often is significant to both the patient and doctor
 Costs, loss of work productivity, and inconvenience
to patients and their families
 Side effects to the patient, such as the small risk of
infection or endophthalmitis
Why different regimens?

9.  Efficacy of monthly dosing in SF CNV in AMD
 Classic and occult
 VIEW: SUB GROUP ANALYSIS
 Outcomes in 12 week injections in second year are similar to 8 week
group
 Prove that individualized treatments necessary
 AMD is a heterogeneous disease that has a
highly variable natural history
MARINA - ANCHOR - VIEW

10.  Patients have different responses to treatment
 Many patients do well without monthly treatment
 HARBOR
 Ranibizumab over 2 years
 93% of patients did not require monthly therapy
 Some patients have a significant injection burden, but some
patients require very few injections over the first 2 years
 Hard to predict
 Because anti-VEGF needs vary significantly between patients
 Don’t know how much VEGF is produced by a given patient or
how much anti-VEGF treatment is required in that maintenance
phase
CATT and HARBOR

11.  Monthly arm of the CATT trial
 Continuous-fixed dosing patients’ rates of
endophthalmitis were almost four- and five-fold higher
than patients in the PRN arm
CATT

12.  5-year CATT data
 Only 50% of the patients had 20/40 or better vision with
PRN
 PRN: Treat patients if there is disease activity
 Potential limitations of PRN
 Recurrence of neovascular leakage
 Growth of lesion size
 Fibrosis
CATT - PRN

13.  LUCAS
 Monthly anti-VEGF injections until the disease was
inactive
 Gradually extended the treatment interval by 2 weeks at
a time to a maximum of 12 weeks
 ?Signs of recurrence, shorten the interval by 2 weeks at
a time
ASRS
American Society of Retina Specialists

14.  Large subretinal bleed:
 Long-term disciform scar
 Could have been prevented with more VEGF suppression
 Multiple recurrences lead to disease progression
 Poorer long-term visual outcomes in some patients
CONCERNS IN AMD
Timeline of progression

15.  Proactive and individualized
 Recurrences less
 Less risk of subretinal fibrosis
 Maximizes long-term visual outcomes
 Safety through fewer injections
 Reduced risk
 glaucoma, geographic atrophy, and endophthalmitis
 cost effective
 Minimizing the drug use, minimizing the time in clinic, and
minimizing lost work productivity of the patient and their
family
TAE
Treat-and-extend

16.  Ability to stretch the interval:
 Much less with bevacizumab (Avastin, Genentech)
 More:
 Ranibizumab (Lucentis,Genentech)
 Aflibercept (Eylea, Regeneron Pharmaceuticals, Inc.)
 Treat-and-extend because
 Not the same with bevacizumab
Branded versus generic drugs

17.  No clear answer on the extension threshold
 ?? Interval stretched up to 16 weeks
 ASRS survey data shows the majority of physicians extend to
12 or fewer weeks
 No clear answer how far patients can be extended
ATLAS

18.  Exiting phase 3 development
 3-month dosing in 50% of patients
 Durability standpoint
 Durability is the key in the treatment of retinal diseases
Brolucizumab
(RTH258, Novartis)

19.  OCT
 OCT-A
 Unexplained drop in visual acuity with no fluid on the OCT
 Segmentation ? Problem; New software a solution
 OCT-A as a biomarker: How many times to retreat a patient
 FA
 Masquerade syndromes
 Repeat FA ? OCT OCT – A a better option
 Fundus autofluorescence
 Indocyanine green fluorescence imaging
Imaging in Retinal Diseases

20.  Traditional fundus camera: 30°
 Mydriatic or non-mydriatic
 EDTRS seven-field and montage
 Not all fundus photography systems have montage
capabilities
 ultrawide-field options
 look at the retina in a graded way and document peripheral
findings
 FFA:
 Phase issues
 FA is time-based, may miss pathologies
IMAGING IN AMD/DME

21.  Is wide-field imaging is absolutely necessary??
 Helps to evaluate about 82% of the entire retinal
surface
 Diabetic changes in the periphery
 Pick up peripheral pathology one can miss miss on
a clinical exam or on traditional montage FAs
Optos
DM, Uveitis & Sickle cell

22.  Uveitis
 because you can look for peripheral vasculitis and
peripheral vascular changes
 Sickle cell disease
 Find areas of nonperfusion
 Pick up small areas of neovascularization
 Nice to have, more you use it, the more you like it
OPTOS

23.  AMD patients: Not much help
 Central serous retinopathy
 Look for peripheral lesions
 Diagnosing patients if they have a scattering of
fluid on the fluorescein
 Guttering on fundus autofluorescence
Other Uses

24. OCT-A
 Noninvasive retinal
angiography without using
extraneous dye
 Advantages over FA
 It takes about 3 to 4
seconds per eye
 Provides all the
information from a regular
OCT (cross-registered
vascular info)
 OCT-A is depth resolved
 Can separate superficial
and deep vascular
plexuses
 Allowing to better
identify the pathology
 FAs are unable to do that

25.  In patients with a questionable CNV lesion on FA
 OCT-A does a nice job of delineating the vascular
plexus
 An ideal way to follow patients to monitor
regression or stabilization of the CNV lesion over
time
OCT-A as a tie-breaker? !!!

26.  Unexplained vision loss
 Widening of the foveal avascular zone
 Difficult to pick up on traditional angiogram
 Motivate patients to make lifestyle changes at the
earliest stages of micro-vascular disease
OCT-A in patients with DME?

27.  AMD treatment can and do achieve long-term
success in managing patients
 Mantra for success
 Patient buy-in
 CATT data, required therapy was 2 years
 Slow decline of vision over time
 Attributable at least in part to under-treatment
LONG-TERM TREATMENT
OUTCOMES IN AMD

28.  Explain to Patients the need to understand that
AMD is a lot like hypertension
 (??Cancer: Remission)
 It is long-term therapy and long-term management
Life Long:
Relentless, Progressive, Degenerative

29.  Difficult to set expectations for the patient up front
 No one ever know how many injections the patient
will need
 . We saw that with the.21,22 At the very least, we
need to convey to patients that longterm monitoring
is absolutely essential.
 Better buy-in with patients with macular
degeneration than the other VEGF-mediated disease
states
HARBOR & CATT data:
AMD unpredictable

30.  Physician tolerance for fluid:
 Patients who are undertreated have chronic fluid
 CATT
 Intraretinal fluid leads to a poorer prognosis than
subretinal fluid
 Wet AMD and dry AMD are not mutually exclusive
 Wet AMD management successful
 But not dry AMD, -progression of atrophy
Unpredictable…...

31.  Small VEGF-binding molecule at a much higher molar
concentration compared to aflibercept
 Behaving the way we would expect something injected
in such a molar excess to behave
 Longer durability
 Cleared from the eye faster
Brolucizumab

32.  Endpoint:
 visual acuity
 NOT OCT-based criteria for retreatment
 Decisions In clinical practice
 Don’t use visual acuity alone
 OCT and sometimes fluorescein
 clinical judgment and our clinical examinations
HAWK and HARRIER
Brolucizumab

33.  Anti-VEGF/anti-angiopoietin-2 bi-specific antibody
 DME
 “Angiopoietin-2 inhibition has a different mechanism of
action
 Some interplay between angiopoietin-2 and VEGF, and this
combination drug may give us the first opportunity to
extend the anti-VEGF effect
 Greater durability or perhaps some vision improvement
 Await the phase 3 clinical trial
Phase 2 study of RG7716 (Genentech)

34.  Prediction: where nAMD therapy in 5, 10, or more years
 Dry macular degeneration
 Soon treatment either geographic atrophy or intermediate
AMD
 Once this is successful, prevent disease progression to
exudative AMD is next step
 Injections still be in use, but not anti-VEGF
 Injecting drugs to slow or prevent disease progression in
dry AMD
 ?? Drug-delivery device : polymers that have anti-VEGF
within them that lasts 6 months with just one injection
Ultimate Moonshot