In AMD, what are the benefits of the newer generation (Vabysmo and Eylea HD) anti-VEGFs over the older generation (Eylea, Avastin)?
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This article is based on the talks from Dr Daniel Martin and Dr Marco Zarbin in the American Academy of Ophthalmology 2024 congress.
Since the initial phase 3 trials (MARINA and ANCHOR) showing the effectiveness of lucentis for the treatment of neovascular age-related macular degeneration (AMD), anti-VEGF therapy has transformed the field of medical retina. Now, there are a number of anti-VEGF therapies available. These can be roughy divided into three categories:
First generation
- lucentis (ranibizumab) - FDA approved in 2006
- avastin (bevacizumab)
Second generation
- eylea (aflibercept 2mg) - FDA approved in 2011
- zaltrap (ziv-aflibercept), off label use in New Zealand
Third generation (approved after 2019 by FDA)
- beovu (brolucizumab)
- vabysmo (faricimab)
- eylea HD (aflibercept 8mg)
There is no visual acuity difference amongst avastin, lucentis, eylea, beovu, eylea HD and vabysmo treatment in AMD
So far, there is no randomised controlled trial showing a difference in visual acuity amongst different anti-VEGF medications. CATT and IVAN compare treatment with avastin and lucentis, and neither the individual trials nor the composite estimate shows a statistically or clinically significant difference in visual acuity outcome.
Similarly, the VIEW 1 and 2 studies compare lucentis to eylea using a fixed dosing regime, and showed no difference in acuity outcome. The RIVAL study comparing lucentis and eylea using a treat-and-extend regime shows a similar result on visual acuity.
The same is observed with HAWK and HARRIER comparing beovu to eylea, TENEYA and LUCERNE comparing vabysmo to eylea, and PULSAR comparing eylea HD to eylea.
Brolucizumab (beovu) is hampered by safety concerns
Brolucizumab has been found to cause vasculitis in a small number of patients. The vasculitis is linked to vascular occlusion, and the prognosis can be poor. The HAWK and HARRIER safety audit shows an overall incidence of 2.1% of vasculitis with vascular occlusion.
Brolucizumab is not approved by MedSafe in New Zealand, and I am not aware of any ophthalmologists who routinely use brolucizumab in New Zealand.
Third generation anti-VEGFs (beovu, vabysmo, eylea HD) have improved durability
It has been accepted that the third generation anti-VEGFs have a greater ability to eliminate fluid and increased durability between injections. The Teneya and Lucerne trials reported around 80% of neovascular AMD patients can be managed on injections more than 12 weeks apart, and around 45% on injections 16 weeks interval with faricimab.
More impressively, the Pulsar study reported 83% of patients can be maintained on injections more than 12 weeks apart, and 78% of patients on aflibercept 8mg (eylea HD) can be maintained on injections every 16 weeks.
However, these results may not be able to be translated directly into clinical practice, as these randomised controlled trials tend to tolerate more fluid at the macula than in routine clinical practice. Furthermore, most clinicians use a treat and extend regime while these randomised controlled trials use a fixed dosing regime (see the discussion on RIVAL in my article on faricimab).
TENEYA / LUCERNE and PULSAR have different trial designs which make direct comparison impossible
The casual observer may conclude that, based on the results from Teneya, Lucerne and Pulsar, eylea HD is more durable than vabysmo. However, there is important difference in the designs within these studies which make direct comparison impossible.
First of all, one needs to look at the much smaller phase 2 study on eylea HD, CANDELA. Interestingly, the result in CANDELA for eylea HD is much less impressive, with only 57% of AMD patients can be managed on injections 12 weeks apart (vs 83% in Pulsar). Why is this the case?
The answer is in the disease assessment criteria.
In CANDELA, active disease for re-treatment is defined by:
- best corrected visual acuity loss of 5 letters OR
- anatomical findings considered vision threatening (new or persistent fluid, new pigment epithelium detachment, haemorrhage, etc)
So, if a patient satisfies one of these two criteria, a repeat treatment will be given.
In PULSAR, the larger phase 3 trial, active disease for re-treatment is defined by:
- best corrected visual acuity loss of 5 letters AND
- anatomical findings considered vision threatening (new or persistent fluid, new pigment epithelium detachment, haemorrhage, etc)
So, a repeat treatment of eylea HD will only be given if a patient satisfies both of these criteria.
Now we need to look at the disease assessment criteria in Teneya and Lucerne, the phase 3 trials for vabysmo. In TENEYA and LUCERNE, active disease for re-treatment is defined by:
- best corrected visual acuity loss of 5 letters OR
- OCT findings of new or persistent fluid, etc OR
- new macular haemorrhage
TENEYA and LUCERNE report that with vabysmo, 78% of AMD patients can be managed with an injection treatment interval of 12 weeks or more. However, if one applies the less stringent disease assessment criteria of PULSAR to TENEYA and LUCERNE, it is estimated that 96% of patients on faricimab can be managed with an injection treatment interval of 12 weeks or more!
The team in Moorfields Eye Hospital hypothetically applied the different disease activity criteria from TENAYA/LUCERNE, HAWK/HARRIER and PULSAR trials to determine the potential impact on the decision to extend treatment intervals at the 4th (week 12) and 5th (week 16) injection visits.
At week 12, proportion of patients with treatment interval extended:
- 80% when applying hypothetical TENAYA/LUCERNE disease activity criteria
- 84% using HAWK/HARRIER criteria
- 94% using PULSAR criteria
At week 16, proportion of patietns with treatment interval extended:
- 78% when applying hypothetical TENAYA/LUCERNE disease activity criteria
- 76% using HAWK/HARRIER criteria
- 100% using PULSAR criteria
How does this information affect my clinical practice?
Often patients would come to me and ask to be on the newest medication, thinking that this will help their vision to improve. I can now confidently tell them that, as long as the exudation is adequately suppressed by their current injections, switching to a different agent will not improve their vision further.
However, I would consider both zaltrap and eylea (if qualifies for special authority) for all my patients with neovascular AMD, given that these second generation medications are likely to be more durable than the first generation medications (lucentis and avastin). In New Zealand, the cost of zaltrap is similar to avastin, and eylea is funded for neovascular AMD if a patient does not respond adequately to avastin.
At this stage, none of the third generation medication is funded, but vabysmo has been approved by MedSafe. For those who have the means to self-fund vabysmo and are unable to extend the treatment interval with eylea, switching to vabysmo is a good option.
Previously, I was more excited about eylea HD, but based on the analysis above, it is unlikely for eylea HD to work significantly better than vabysmo for most patients with neovascular AMD.
About Dr Leo Sheck
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Dr Sheck is a RANZCO-qualified, internationally trained ophthalmologist. He combined his initial training in New Zealand with a two-year advanced fellowship in Moorfield Eye Hospital, London. He also holds a Doctorate in Ocular Genetics from the University of Auckland and a Master of Business Administration from the University of Cambridge. He specialises in medical retina diseases (injection therapy), cataract surgery, ocular genetics, uveitis and electrodiagnostics.
