1. Key Developments From Recent Clinical Trials
nAMD – A Year in Review
Key Developments From Recent Clinical Trials
Moderator
Panelist
Timothy Y. Lai, MD, FRCS, FRCOphth
Director, 2010 Retina & Macula Centre
Honorary Clinical Associate Professor
Department of Ophthalmology & Visual Sciences
The Chinese University of Hong Kong
Kowloon, Hong Kong SAR
Annabelle A. Okada, MD, DMSc
Professor of Ophthalmology
Department of Ophthalmology
Kyorin University School of Medicine
Tokyo, Japan

2. This program may include a discussion of data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal

3. Challenges With Current Therapy: Administration
High injection frequency leads to high patient volume
Creates backlog of patients
Burden to staff
Burden to patient
Financial burden
Treatment not covered by insurance in some countries

4. Challenges With Current Therapy: Regimens
Treat and extend (T&E)
Proactive treatment
Compared to reactive PRN
PRN leads to more visits, more injections
Patients relapse, need to start over from 4-week injection interval
Reduces patient volume
Patients are treated at every visit
Upper limit of extend period is unclear
Some patients extended to 12, 14, or 16 weeks
T&E = treat and extend
PRN = pro re nata (ie, "as needed")

5. Polypoidal Choroidal Vasculopathy
22.3% to 61.6% of nAMD in Asia are PCV[a]
Two important trials in PCV
EVEREST II[b]
Intravitreal ranibizumab ± vPDT
At 12 months compared with ranibizumab monotherapy:
Significantly better VA
Fewer intravitreal ranibizumab injections
PLANET[c]
Aflibercept ± rescue vPDT for patients with PCV
Study Start Date: May 2014
Estimated Study Completion Date: July 2017
nAMD = neovascular age-related macular degeneration
PCV = polypoidal choroidal vasculopathy
VA = visual acuity
vPDT = verteporfin photodynamic therapy
a. Wong CW, et al. J Clin Med. 2015;4: ; b. Koh A, et al. JAMA Ophthalmol. 2017;135: ; c. Lee WK, et al. ARVO Oral presentation.

6. EVEREST II: Ranibizumab ± vPDT in Patients With PCV
Study Design[a]
BCVA = best corrected visual acuity
PCV = polypoidal choroidal vasculopathy
PRN = pro re nata (ie, "as needed")
vPDT = verteporfin photodynamic therapy
Results at 12 months[b]
BCVA, letters
Complete Polyp Regression, %
Ranibizumab + vPDT
8.3
69.3
Ranibizumab (single)
5.1
34.7
a. Koh A, et al. AAO b. Koh A, et al. JAMA Ophthalmol. 2017;135:

7. PCV: Safety With PDT
PCV first described as a hemorrhagic exudative macular degeneration
Polypoidal lesions by indocyanine green angiography
PDT results in complete regression in 71% to 95% of cases
Stable or improved vision in up to 95% of cases
PDT associated with 2.2% to 31% hemorrhagic complications
PCV = polypoidal choroidal vasculopathy
PDT = photodynamic therapy
Rishi P, et al. Indian J Ophthalmol. 2017;65:

8. PLANET: Aflibercept ± Rescue vPDT
Patients not requiring vPDT,
P = .84
BCVA (letters)
Absence of active polyps
89.7%
10.7
38.9%
85.7%
10.8
44.8%
Patients with PCV
(N = 318)
3 monthly injections
Aflibercept
± vPDT (rescue)
Aflibercept with sham PDT (PRN) was noninferior to aflibercept with rescue vPDT at 52 weeks
Similar incidence of ocular treatment-emergent AEs between groups (31.2% vs 29.2% sham PDT and rescue vPDT groups, respectively)
Ongoing study
AEs = adverse events
BCVA = best corrected visual acuity
PCV = polypoidal choroidal vasculopathy
PRN = pro re nata (ie, "as needed")
vPDT = verteporfin photodynamic therapy
Lee WK, et al. ARVO Oral presentation.

9. ALTAIR: Aflibercept T&E by 2- or 4-Week Increments
Patients with nAMD
(N = 255)
Injections
Weeks 0, 4, 8, 16
Aflibercept, adjust by 2-week intervals
Aflibercept, adjust by 4-week intervals
Weeks 24 to 96
Patients:
Japanese adults, ≥ 50 y of age, treatment-naïve nAMD, active CNV, baseline BCVA 25 to 73 letters
PCV: 37.4% 2-week interval, 35.8% 4-week interval
Primary endpoint:
Change from baseline BCVA at 52 weeks
nAMD = non-age-related macular degeneration
BCVA = best corrected visual acuity
CNV = choroidal neovascularization
T&E = treat and extend
Okada AA, et al. AAO Oral presentation.

10. ALTAIR: T&E Criteria Dry macula extend interval
Extension
Maintenance
Shortening
No fluid on OCT
AND
Loss < 5 letters
Increase < 100 μm CRT
No new neovascularization
No new macular hemorrhage
Fluid decrease on OCT
New fluid on OCT OR
Fluid ≥ baseline on OCT
Loss ≥ 5 letters
Increase ≥ 100 μm CRT
New neovascularization
New macular hemorrhage
CRT = central retinal thickness
OCT = optical coherence tomography
T&E = treat and extend
Dry macula extend interval
Trending toward dry maintain current interval
Worsening shortening interval
Minimum extension: 8 weeks
Maximum extension: 16 weeks
Okada AA, et al. AAO Oral presentation.

11. ALTAIR: Change in BCVA With Time
Mean change in BCVA from
baseline (letters) 10 12 8 6 4 2 16 20 24 28 32 36 40 44 48 52
5.0
6.7
8.4
9.1
9.4
9.6
9.2
9.0
4.3
8.8
8.3
8.1
LS mean (95% CI) difference at Week 52: -0.4 (-3.8 to 3.0)
2-week intervals
4-week intervals
BCVA = best corrected visual acuity
Weeks
Okada AA, et al. AAO Oral presentation.

12. ALTAIR: Central Retinal Thickness
Mean change in CRT (UM) from
baseline
-50
-100
-150 4 8 12 16 20 24 28 32 36 40 44 48 52
LS mean (95% CI) difference at Week 52: -5.8 (-24.3 to 12.7)
2-week intervals
4-week intervals
-99.7
-100.1
-105.7
-104.0
-116.1
-117.6
-121.3
-126.1
-106.2
BCVA = best corrected visual acuity
-123.7
-127.1
-130.8
-130.9
-132.4
-129.5
-134.4
Weeks
Okada AA, et al. AAO Oral presentation.

13. ALTAIR: Injection Intervals
2-week Interval
(n = 123)
4-week Interval (n = 123)
Number of injections, mean (SD)
7.2 (0.9)
6.9 (1.0)
Last interval before Week 52
Mean (SD)
10.7 (2.7)
11.8 (3.7)
> 8 weeks, n (%)
72 (58.5)
74 (60.2)
≥ 12 weeks, n (%)
52 (42.3)
61 (49.6)
16 weeks, n (%)
50 (40.7)
Next scheduled interval determined at the last visit
n = 111
n = 116
12.0 (3.4)
12.1 (3.5)
76 (68.5)
76 (65.5)
63 (56.8)
67 (57.8)
39 (35.1)
47 (40.5)
Okada AA, et al. AAO Oral presentation.

14. ALTAIR: Adverse Events
IAI-2W, n (%) (n = 124)
IAI-4W, n (%) (n = 123)
Any TEAE
67 (54.0)
59 (48.0)
Ocular TEAE (study eye)
14 (11.3)
19 (15.4)
Conjunctival hemorrhage
3 (2.4)
7 (5.7)
Retinal pigment epithelial
tear
Nonocular TEAE
52 (41.9)
49 (39.8)
Nasopharyngitis (study
eye)
16 (12.9)
13 (10.6)
Serious TEAEs
12 (9.7)
12 (9.8)
Ocular serious TEAE (study eye)
Nonocular serious TEAEs
11 (8.9)
Death
2 (1.6)
BCVA = best corrected visual acuity
Okada AA, et al. AAO Oral presentation.

15. ALTAIR: Summary
Both T&E regimens improve BCVA and anatomic outcomes[a]
Similar improvement through week 52
55% had achieved an interval of ≥ 12 weeks
40% achieved 16 weeks (maximum allowed interval)
Findings in line with Asia-Pacific recommendations[b]
Aflibercept dosing intervals can be extended by 4 weeks at a time after 3-month loading dose
May be extended to 8- or 12-week intervals in patients with inactive disease
BCVA = best corrected visual acuity
T&E = treat and extend
a. Okada AA, et al. AAO Oral presentation; b. Koh A, et al. Asia Pac J Ophthalmol (Phila). 2017;6:

16. Treatment in the Real World: LUMINOUS
Real-world data is not usually as dramatic as seen in the clinical setting
Patients need to keep up with injections
LD = loading dose
(n = 537) (n = 1,924) (n = 918) (n = 224)
Holz FG, et al. EURETINA Oral Presentation.

17. Emerging Agents: Brolucizumab
Noninferior to aflibercept
26 kDa, single chain antibody fragment (scFv)
Molar dose equivalent to to 13.3-fold aflibercept
Superior anatomic changes compared to aflibercept
HAWK trial
Mean change in BCVA, letters (SE)
P Value for Noninferiority
Brolucizumab 3 mg (n = 358)
6.1 (0.69)
0.0003
Brolucizumab 6 mg (n = 360)
6.6 (0.71)
< .0001
Aflibercept 2 mg (n = 360)
6.8 (0.71)
HARRIER trial
Brolucizumab 6 mg (n = 370)
6.9 (0.61)
Aflibercept 2 mg (n = 369)
7.6 (0.61)
BCVA = best corrected visual acuity
kDa = kilodaltons
scFv = single chain antibody fragment
SE = standard error
a Noninferiority with a 4.0 letter margin vs aflibercept.
b Noninferiority for change in BCVA from baseline averaged over period of Week in HAWK (brolucizumab 3 mg, P = .0001; brolucizumab 6 mg, P <.0001) and HARRIER (P = .0003) vs aflibercept.
Dugel P, et al. AAO Oral presentation.

18. Emerging Agents: Early Stage
Angiopoietins
Key regulator of adult vascular homeostasis[a]
Regulates vascular remodeling and maturation[a]
Agents under investigation[b]
RG7716, ARP-1536, and nesvacumab
Other agents and therapies[b]
Anti-VEGF: abicipar pegol, OPT-302, topicals
Anti-PDGF: pegpleranib and rinucumab
Both failed to show consistently improved visual outcomes compared to anti-VEGF monotherapy
Sustained-release anti-VEGF delivery treatments
a. Bolinger MT, et al. Int J Mol Sci. 2016;17:1498; b. Hussain RM, et al. Expert Opin Emerg Drugs. 2017;22:

19. Summary Anti-VEGF improves visual acuity in patients with PCV
EVEREST II and PLANET
T&E is a clinically useful approach
Possible to extend treatment intervals faster
Reduces burden on office staff and patients
New agents
Brolucizumab
Angiopoietins
PCV = polypoidal choroidal vasculopathy
T&E = treat and extend

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