Eylea – the first major treatment for wet age-related macular degeneration to be introduced in Australia in the past five years – has the potential to change the game for Australian ophthalmologists.
Intravitreal anti-vascular endothelial growth factor (VEGF) injections have revolutionised the treatment of wet age-related macular degeneration (AMD). These drugs work by blocking the actions of VEGF, a substance important in the pathogenesis of wet AMD due to its ability to stimulate abnormal blood vessel growth underneath the retina.
Until recently, the only anti-VEGF agents available for ocular use in Australia were Avastin (bevacizumab) and Lucentis (ranibizumab). Avastin is a full-length monoclonal antibody to VEGF whereas Lucentis is a monoclonal antibody fragment to VEGF. The suffix ‘mab’ in bevacizumab and ranibizumab indicates that they are monoclonal antibody derivatives. Both drugs have been widely used for treating wet AMD in Australia since 2006 and 2007 respectively.
Eylea (aflibercept) is a new anti-VEGF drug and the first major treatment for wet AMD to be introduced into Australia in the past five years. It was recently listed on the Pharmaceutical Benefits Scheme (PBS) from 1 December 2012. Eylea is a soluble decoy receptor produced by fusing DNA sequences from VEGF receptors onto an antibody backbone (known as the Fc region). The suffix ‘cept’ in aflibercept indicates a receptor fusion protein.
Surveys have indicated that the majority of US retinal specialists now prefer Eylea over Lucentis for treating wet AMD
Eylea differs from Avastin and Lucentis in that it has a significantly higher binding affinity to VEGF and has an additional mechanism of action by blocking the effects of a substance related to VEGF called placental growth factor. Like Avastin and Lucentis, Eylea is administered via intravitreal injection. Theoretical mathematical modeling predicts that a single intravitreal injection of Eylea would last between six to 12 weeks in human eyes compared to four weeks for Lucentis – although this has not yet been confirmed in pharmacokinetic studies. Eylea offers the potential to achieve similar efficacy and safety results with less frequent treatment than Lucentis.
VIEW 1 & 2 Trials
The efficacy and safety of Eylea in treating wet AMD has been proven in large international multi-centre randomised stage 3 clinical trials known as VIEW 1 and VIEW 2 (VEGF trap-eye: Investigation of Efficacy and safety in Wet AMD trials 1 and 2).
The two studies were related and identical in design with VIEW 1 conducted in North America by Regeneron, and VIEW 2 conducted in Europe, Asia, Australia, Japan, and South America by Bayer. There were seven clinical trial sites in Australia with enrolment commencing in 2008. The VIEW studies represent the largest wet AMD treatment trials ever conducted with 2,457 patients enrolled.
The primary endpoint of the VIEW studies was the percentage of patients who maintained visual acuity (VA) – defined as loss of less than 15 letters (three lines) on an ETDRS chart – at one year.
Patients with wet AMD involving the foveal centre were randomised into four groups: 0.5mg or 2mg Eylea every four weeks, 2mg Eylea every eight weeks (after three initial monthly injections), or Lucentis 0.5mg every four weeks. After one year, patients continued to be treated with the same drug and dosage at least every three months, with additional injections being performed as needed depending upon the results of clinical examination and retinal imaging.
Because the current commercial preparation of Eylea contains aflibercept 2mg, recommended every eight weeks, this is the group that most attention has focused on, in comparison with the group on Lucentis every four weeks.
Clinical Trial Results
The mean patient age was 76 years. The primary endpoint, maintenance of VA at one year, was achieved in 94 per cent of patients treated with Eylea 2mg every eight weeks compared to 95 per cent of patients treated with Lucentis every four weeks. The difference between groups was not statistically significant.
The mean improvement in VA in patients treated with Eylea 2mg every eight weeks was 8.4 letters at one year and 7.6 letters at week 96, with a mean of 11.2 injections over the two years of the study, including 4.2 injections in year two. In eyes treated with monthly Lucentis, the mean improvement in VA was 8.7 letters at one year and 7.9 letters at week 96, with a mean 16.5 injections over the two years of the study, including 4.7 injections in year two.
There was a good anatomic response to treatment in all groups with a rapid decrease in macular thickness (measured by optical coherence tomography scanning) being maintained over the two years of the study.
There were no significant differences in ocular or systemic safety profiles between Eylea and Lucentis. Both drugs demonstrated a similar incidence of complications related to the injection procedure (e.g. endophthalmitis) and a similar incidence of arterial thrombotic events (e.g. stroke or heart attacks) of between 3.2 to 3.3 per cent. No unexpected safety signals were detected.
Preliminary data from other trials indicate that Eylea may also be a potentially effective treatment for retinal vein occlusions and diabetic macular oedema, but it is not yet approved or funded for these indications.
Real World Experience
Eylea has been available commercially in the United States since November 2011 and early reports regarding its use have been encouraging. At the American Society of Retinal Specialists annual meeting in August 2012 there were 10 abstracts from different US centres, all reporting favourable treatment results with Eylea for wet AMD. These included numerous reports of improved visual and anatomic results in patients who had switched treatment from Lucentis to Eylea after experiencing suboptimal results with Lucentis. Surveys have indicated that the majority of US retinal specialists now prefer Eylea over Lucentis for treating wet AMD. The share price for Regeneron pharmaceuticals (NASDAQ:REGN), the company that markets Eylea in the US, has risen quickly from under USD25c in October 2010 to over USD180c in December 2012 as a result of the commercial success of Eylea.
Implications for clinical practice in Australia
Until recently, the gold standard treatment for wet AMD was Lucentis administered via monthly intravitreal injections. This enables a majority of patients treated for wet AMD to maintain their VA. However, monthly treatment is associated with a significant burden on patients, their carers, doctors and the healthcare system. In clinical practice, the majority of patients with wet AMD are not being treated with monthly injections due to logistic issues and also because data from clinical trials such as the CATT trial indicates that similar visual results can be gained from less frequent treatment.
Australian Medicare data shows that a new patient with wet AMD receives an average of 7.4 Lucentis injections in their first year of treatment.
The recommended treatment regime for Eylea is injection every eight weeks after an initial induction course of three monthly injections. Awareness about Eylea among AMD patients currently receiving Lucentis treatment is growing rapidly due to reports in the news media and information provided by organisations such as the Macular Degeneration Foundation. Many of my own patients had been eagerly awaiting the PBS listing of Eylea in the hope that it may enable them to require fewer injections to maintain their vision. For patients, the costs and injection procedure associated with an Eylea injection are identical to that with Lucentis.
The use of Eylea among Australian ophthalmologists will vary, with some continuing to use Lucentis as first line treatment due to its longer clinical track record and reserving Eylea for patients that respond poorly to Lucentis. Others will turn to Eylea in preference to Lucentis as their first line treatment due to the potential need for fewer injections.
Conclusions
Eylea injected every eight weeks is clinically equivalent to Lucentis injected every four weeks for maintaining VA (less than 15 letters of vision loss) over one year in patients with wet AMD. Encouraging early data from the US suggests that Eylea may be particularly beneficial in some patients that have responded incompletely to Lucentis.
The recent listing of Eylea on the PBS is a welcome and potentially game changing addition to our options for treating wet AMD.
Dr. Simon Chen MBBS, BSc, FRCOphth, FRANZCO is a retinal specialist. He has particular expertise in intravitreal anti-VEGF therapy and sutureless vitreoretinal surgery. He is a principal investigator for numerous international clinical trials of novel treatments for retinal disease and was the primary investigator for the VIEW 2 trial at Vision Eye Institute Chatswood, which commenced in 2008. Dr. Chen practises at Vision Eye Institute clinics across Sydney.
