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Anti-VEGF treatment in Age-related Macular Degeneration

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Last updated: July 19th, 2022

Summary of Evidence
Evidence
References
Comments

Summary of Evidence

Ranibizumab

Ranibizumab vs sham

Ranibizumab prevented vision loss and improved mean visual acuity in patients with minimally classic or occult CNV secondary to AMD.(MARINA, 2006).{Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1419-31.}

Ranibizumab vs Photodynamic therapy

Ranibizumab provided greater clinical benefit than verteporfin PDT in patients with predominantly classic CNV secondary to AMD.(ANCHOR, 2009).{Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T; ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009 Jan;116(1):57-65.e5.}

Aflibercept

Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab at one year.(VIEW, 2012).{Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012 Dec;119(12):2537-48.}

Bevacizumab

Bevacizumab vs Ranibizumab

Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period.(CATT, 2012).{Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, Toth C, Redford M, Ferris FL 3rd. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012 Jul;119(7):1388-98.}

Brolucizumab

Brolucizumab vs Aflibercept

Brolucizumab was noninferior to aflibercept in visual function at Week 96.(HAWK/HARRIER, 2021).{Dugel PU, Singh RP, Koh A, Ogura Y, Weissgerber G, Gedif K, Jaffe GJ, Tadayoni R, Schmidt-Erfurth U, Holz FG. HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2021 Jan;128(1):89-99.}

Evidence

1. General

1.1 Natural history

Review

2008 Wong et.al.

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2008
Review

A doubling of the visual angle of presenting VA may be expected to occur in the year after initial presentation in eyes with untreated neovascular AMD. No conclusions can be drawn as to the differences in rates of disease progression by neovascular AMD subtype. {Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, Fahrbach K, Probst C, Sledge I. The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology. 2008 Jan;115(1):116-26.}

1.2 Principles of management

Consensus statement

2014 Schmidt-Erfurth et.al.

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2014
Consensus statement

Expert guidance for diagnostic and therapeutic management of neovascular AMD by the European Society of Retina Specialists.{Schmidt-Erfurth U, Chong V, Loewenstein A, Larsen M, Souied E, Schlingemann R, Eldem B, Monés J, Richard G, Bandello F; European Society of Retina Specialists. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol. 2014 Sep;98(9):1144-67.}

Schmidt-Erfurth et.al.
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1.2.1 Anti-VEGF therapy

Review

2018 Mehta et.al.

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2018
Review

Real-world observations relating to efficacy, safety and resource utilisation of intravitreal anti-VEGF therapy for neovascular AMD are described. Real-world registries could be used by drug regulatory authorities and industry as an alternative to more costly and time-consuming phase 4 clinical trials, potentially allowing medication costs to be based on outcomes achieved.{Mehta H, Tufail A, Daien V, Lee AY, Nguyen V, Ozturk M, Barthelmes D, Gillies MC. Real-world outcomes in patients with neovascular age-related macular degeneration treated with intravitreal vascular endothelial growth factor inhibitors. Prog Retin Eye Res. 2018 Jul;65:127-146.}

1.2.1.1 Treatment end point

Clinical Trial

2019 Guymer et.al. (FLUID)

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2019
Clinical Trial

Patients treated with a ranibizumab treat-and-extend protocol who tolerated some subretinal fluid (SRF) achieved visual acuity that is comparable, with fewer injections, with that achieved when treatment aimed to resolve all SRF completely.{Guymer RH, Markey CM, McAllister IL, Gillies MC, Hunyor AP, Arnold JJ; FLUID Investigators. Tolerating Subretinal Fluid in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab Using a Treat-and-Extend Regimen: FLUID Study 24-Month Results. Ophthalmology. 2019 May;126(5):723-734.}

Randomized controlled trial of Ranibizumab intensive (complete resolution of SRF and intraretinal fluid) vs relaxed (resolution of intraretinal fluid only) in CNV secondary to AMD (279 patients)
Findings (2-years):
- The relaxed treatment arm demonstrated non-inferior BCVA improvement from baseline to month 24 compared with the intensive treatment arm.
- Participants in the relaxed group received fewer ranibizumab injections over 24 months than those in the intensive group (mean 15.8 vs 17).

		Intensive	Relaxed
Visual outcomes	Mean BCVA change from baseline to month 24 (letters)	3.0	2.6
	Proportion with 20/40 or better VA	53.5%	56.6%
	Proportion with 20/200 or worse VA	8.7%	8.1%
Number of injections		17.0	15.8
Intervals	Porportion that did not extend beyond 4-week intervals	13.5%	2.8%
	Porportion that extended to and maintained 12-week	15.0%	29.6%

2. Ranibizumab

Consensus statement

2010 Mitchell et.al.

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2010
Consensus statement

Evidence-based and consensus recommendations for treatment indication and assessment, retreatment and monitoring for Ranibizumab in neovascular age-related macular degeneration.{Mitchell P, Korobelnik JF, Lanzetta P, Holz FG, Prünte C, Schmidt-Erfurth U, Tano Y, Wolf S. Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol. 2010 Jan;94(1):2-13.}

2.1 Ranibizumab vs sham

Clinical Trial

2010 Abraham et.al. (PIER)

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2010
Clinical Trial

Ranibizumab provided significant VA benefit in patients with CNV secondary to AMD compared to sham.{Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol. 2010 Sep;150(3):315-324.e1.}

Randomized controlled trial of Ranibizumab vs sham in CNV secondary to AMD (184 patients)
Findings (2-years):
- VA of sham patients who crossed over to ranibizumab had an average loss of 3.5 letters 10 months after crossover.
- VA of ranibizumab 0.3 mg and 0.5 mg group patients who rolled over to monthly ranibizumab increased on average by 2.2 and 4.1 letters, respectively, 4 months after rollover.

Outcomes	Sham injection	IVR 0.3mg	IVR 0.5mg
VA change (letters) from baseline	-21.4	-2.2	-2.3

Clinical Trial

2006 Rosenfeld et.al. (MARINA)

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2006
Clinical Trial

Ranibizumab prevented vision loss and improved mean visual acuity in patients with minimally classic or occult CNV secondary to AMD.{Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1419-31.}

Randomized controlled trial of Ranibizumab vs sham in minimally classic or occult CNV secondary to AMD (716 patients)
Findings (5-years):

Outcomes	Group	Sham	RAN 0.3mg	RAN 0.5mg
Lost < 15 letters from baseline	12 months	62.2%	94.5%	94.6%
	24 months	52.9%	92.0%	90.0%
Gained ≥ 15 letters		5.0%	24.8%	33.8%
VA change (letters)	12 months	-10.4	+6.5	+7.2
	24 months

Rosenfeld et.al. (MARINA)
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2.2 Ranibizumab vs PDT

Clinical Trial

2009 Brown et.al. (ANCHOR)

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2009
Clinical Trial

Ranibizumab provided greater clinical benefit than verteporfin PDT in patients with predominantly classic CNV secondary to AMD.{Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T; ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009 Jan;116(1):57-65.e5.}

Randomized controlled trial of Ranibizumab vs Verteporfin PDT in predominantly classic subfoveal CNV secondary to AMD (423 patients)
Findings (2-years):

Outcomes	PDT	RAN
Lost < 15 letters from baseline	65.7%	89.9-90.0%
Gained ≥ 15 letters	6.3%	34.0-41.0%
VA change (letters)	-9.8	+8.1 to 10.7

2.3 Ranibizumab vs Bevacizumab

Clinical Trial

2016 Silva et.al. (TREND)

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2016
Clinical Trial

Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Vision gains during the first 2 years however were not maintained at 5 years.{Silva R, Berta A, Larsen M, Macfadden W, Feller C, Monés J; TREND Study Group. Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration: Results with Ranibizumab from the TREND Study. Ophthalmology. 2018 Jan;125(1):57-65.}

Randomized controlled trial of Ranibizumab vs Bevacizumab in CNV secondary to AMD (1107 patients)
Findings (2-years):
- Mean gain in VA was similar for both drugs (5.0-8.8 letters, bevacizumab-ranibizumab difference = −1.4 letters].
- Mean VA gain was greater for monthly than for as-needed treatment (difference = −2.4 letters)
- Rates of death and arteriothrombotic events were similar for both drugs
Findings (5-years):
- Vision gains during the first 2 years were not maintained; at 5 years 50% of eyes had VA of 20/40 or better and 20% had VA of 20/200 or worse.
- Mean change in VA was −3 letters from baseline and −11 letters from 2 years.

Clinical Trial

2012 Maguire et.al. (CATT)

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2012
Clinical Trial

Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period.{Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, Toth C, Redford M, Ferris FL 3rd. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012 Jul;119(7):1388-98.}

Randomized controlled trial of Ranibizumab vs Bevacizumab in CNV secondary to AMD (1107 patients)
Findings (2-years):
- Mean gain in VA was similar for both drugs (5.0-8.8 letters, bevacizumab-ranibizumab difference = −1.4 letters].
- Mean VA gain was greater for monthly than for as-needed treatment (difference = −2.4 letters)
- Rates of death and arteriothrombotic events were similar for both drugs

2.4 Ranibizumab dosing regime

Clinical Trial

2018 Maguire et.al. (CATT)

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2018
Clinical Trial

Ranibizumab 0.5 mg administered according to a treat-and-extend was statistically noninferior and clinically comparable with a monthly regimen in improving visual acuity from baseline to the end of study

Randomized controlled trial of Ranibizumab 0.5mg treat-and-extend regimen vs monthly regimen in CNV secondary to AMD (650 patients)
Findings (1-year):
- The T&E regimen was noninferior to the monthly regimen, with mean BCVA change from baseline of 6.2 versus 8.1 letters respectively.
- Fewer injections were required in patients receiving the T&E (8.7) versus monthly (11.1) regimen.

Review

2016 Chin-Yee et.al.

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2016
Review

Systematic review of 70 studies suggests superiority of the treat and extend regimen to PRN treatment in a 12-month period. There is a need for randomised clinical trials to confirm these findings and to evaluate long-term efficacy outcomes with these regimens compared with monthly therapy.{Chin-Yee D, Eck T, Fowler S, Hardi A, Apte RS. A systematic review of as needed versus treat and extend ranibizumab or bevacizumab treatment regimens for neovascular age-related macular degeneration. Br J Ophthalmol. 2016 Jul;100(7):914-917.}

3. Aflibercept

3.1 Aflibercept vs Ranibizumab

Clinical Trial

2012 Heier et.al. (VIEW)

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2012
Clinical Trial

Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab at one year.{Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012 Dec;119(12):2537-48.}

Randomized controlled trial of Aflibercept vs Ranibizumab in CNV secondary to AMD (2419 patients)
Findings (1-year):
- All aflibercept groups were noninferior to monthly ranibizumab in maintaining vision at 52 weeks (losing <15 letters)

Outcomes	AFLI 0.5q4	AFLI 2q4	AFLI 2q4	RAN
Lost < 15 letters	95.1-95.6%	95.9-96.3%	95.1-95.6%	94.4%

3.2 Aflibercept dosing regime

Clinical Trial

2020 Ohji et.al. (ALTAIR)

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2020
Clinical Trial

Intravitreal Aflibercept administered using two different treat-and-extend regimens for CNV secondary to AMD improved functional and anatomic outcomes at week 52 and outcomes were maintained to week 96.{Ohji M, Takahashi K, Okada AA, Kobayashi M, Matsuda Y, Terano Y; ALTAIR Investigators. Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR : A Randomized Controlled Trial. Adv Ther. 2020 Mar;37(3):1173-1187.}

Randomized controlled trial of Aflibercept treat-and-extend regime with 2-week vs 4-week adjustments in CNV secondary to AMD (246 patients)
Findings (2-years):

Outcomes	Time	AFLI 2 week interval	AFLI 4 week interval
Mean no. of injections	52 weeks	7.2	6.9
	96 weeks	10.4	10.4
Mean last injection interval (weeks)	96 weeks	10.7	11.8
Mean VA change( letters)	96 weeks	+7.6	+6.1

4. Bevacizumab

4.1 Bevacizumab vs Ranibizumab

Clinical Trial

2016 Maguire et.al. (CATT)

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2016
Clinical Trial

Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Vision gains during the first 2 years however were not maintained at 5 years.{Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire MG, Martin DF, Ying GS, Jaffe GJ, Daniel E, Grunwald JE, Toth CA, Ferris FL 3rd, Fine SL. Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016 Aug;123(8):1751-1761.}

Randomized controlled trial of Ranibizumab vs Bevacizumab in CNV secondary to AMD (1107 patients)
Findings (2-years):
- Mean gain in VA was similar for both drugs (5.0-8.8 letters, bevacizumab-ranibizumab difference = −1.4 letters].
- Mean VA gain was greater for monthly than for as-needed treatment (difference = −2.4 letters)
- Rates of death and arteriothrombotic events were similar for both drugs
Findings (5-years):
- Vision gains during the first 2 years were not maintained; at 5 years 50% of eyes had VA of 20/40 or better and 20% had VA of 20/200 or worse.
- Mean change in VA was −3 letters from baseline and −11 letters from 2 years.

Clinical Trial

2012 Maguire et.al. (CATT)

Article link | Archive link | Metrics

2012
Clinical Trial

Randomized controlled trial of Ranibizumab vs Bevacizumab in CNV secondary to AMD (1107 patients)
Findings (2-years):
- Mean gain in VA was similar for both drugs (5.0-8.8 letters, bevacizumab-ranibizumab difference = −1.4 letters].
- Mean VA gain was greater for monthly than for as-needed treatment (difference = −2.4 letters)
- Rates of death and arteriothrombotic events were similar for both drugs

5. Brolucizumab

5.1 Brolucizumab vs Aflibercept

Clinical Trial

2020 Dugel et.al. (HAWK/HARRIER)

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2020
Clinical Trial

Brolucizumab was noninferior to aflibercept in visual function at Week 96.{Dugel PU, Singh RP, Koh A, Ogura Y, Weissgerber G, Gedif K, Jaffe GJ, Tadayoni R, Schmidt-Erfurth U, Holz FG. HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2021 Jan;128(1):89-99.}

Randomized controlled trial of Brolucizumab vs Aflibercept in CNV secondary to AMD (1078/739 patients)
Findings (2-years):
- Brolucizumab was noninferior to aflibercept in visual function at Week 96
- At week 92 there was a 45.4% and 38.6% probability for brolucizumab 6mg patients of maintaining on q12w in HAWK and HARRIER, respectively.

Outcomes	Group	BRO 3mg	BRO 6mg	AFLI 2mg
VA change	HAWK	+5.6	+5.9	+5.3
	HARRIER		+6.1	+6.6

Dugel et.al. (HAWK/HARRIER)
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5.2 Safety data

Clinical Trial

2021 Mones et.al. (HAWK/HARRIER)

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2021
Clinical Trial

A post hoc analysis of a subset of data from the HAWK and HARRIER clinical trials showed that

The incidence of definite/probable intraocular inflammation (IOI) was 4.6% (IOI + vasculitis, 3.3%; IOI + vasculitis + occlusion, 2.1%).
There were 8 cases (incidence 0.74%) of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes with IOI
Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%. {Monés J, Srivastava SK, Jaffe GJ, Tadayoni R, Albini TA, Kaiser PK, Holz FG, Korobelnik JF, Kim IK, Pruente C, Murray TG, Heier JS. Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion-Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER. Ophthalmology. 2021 Jul;128(7):1050-1059.}

Mones et.al. (HAWK/HARRIER)
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Anti-VEGF treatment in Age-related Macular Degeneration

Summary of Evidence

Evidence

1. General

1.1 Natural history

1.2 Principles of management

1.2.1 Anti-VEGF therapy

1.2.1.1 Treatment end point

Details

2. Ranibizumab

2.1 Ranibizumab vs sham

Details

Details

2.2 Ranibizumab vs PDT

Details

2.3 Ranibizumab vs Bevacizumab

Details

Details

2.4 Ranibizumab dosing regime

Details

3. Aflibercept

3.1 Aflibercept vs Ranibizumab

Details

3.2 Aflibercept dosing regime

Details

4. Bevacizumab

4.1 Bevacizumab vs Ranibizumab

Details

Details

5. Brolucizumab

5.1 Brolucizumab vs Aflibercept

Details

5.2 Safety data

References

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