Introduction of an anti-VEGF

Historically great expectations

The first ophthalmic anti-VEGF drug, pegaptanib (Macugen, Ophthotech, New York, USA), was introduced in early 2005 with great expectations. However, for a couple of possible reasons - lack of panVEGFA binding and binding to the heparin (not the receptor) binding site of VEGF - this aptamer to VEGF₁₆₅ produced disappointing results. But surgeons were not dissuaded from using anti-VEGF drugs because, quickly on the heals of pegaptanib, the highly effective full-length antibody (bevacizumab, Avastin, Genentech, S. San Francisco, California, USA/Roche, West Sussex, UK) and antibody fragment (ranibizumab, Lucentis, Genentech, S. San Francisco, California, USA/Novartis, Basel, Switzerland) were introduced, both of which bind all isoforms of VEGF-A.

Trial results

During phase 1 and 2 exudative AMD trials, the higher doses of aflibercept resulted in excellent gains in vision and hinted at a prolonged duration of action.^2–4 These studies were followed by the concurrent VIEW 1 (North America) and VIEW 2 (South America, Europe, Asia and Australia) trials, which enrolled a total of 2457 patients, the most AMD patients ever studied. Patients were randomized to 3 dosing regimens of aflibercept (0.5 mg every 4 weeks, 2 mg every 4 weeks, 2 mg every 8 weeks) or ranibizumab 0.5 mg every 4 weeks. All investigational arms met the primary endpoint - prevention of 15 letters loss of vision (aflibercept: 95% to 96% vs ranibizumab: 94%). Furthermore, integrated data from both trials showed that aflibercept met the secondary endpoints - letters of vision gained (aflibercept: +8.3 to +9.4 vs ranibizumab: +8.7; p > 0.05) and macular thinning (aflibercept: –123 µm to –139 µm vs ranibizumab - 128 µm; p > 0.05).⁵

Many investigators thought that aflibercept's high affinity for VEGF would result in greater biological activity and superior gains in vision compared to bevacizumab and ranibizumab. When the vision gains from the VIEW 1 were tabulated (aflibercept 2 mg every 4 weeks: +10.9 letters vs ranibizumab: +8.1 letters; p < 0.001) investigators thought they had a drug which improved vision more than ranibizumab. One week later, however, the finalized VIEW 2 results showed that the high dose aflibercept group performed the worst against ranibizumab (+7.6 letters vs +9.4 letters; p > 0.05). Integrated data suggested that the VIEW 1 results were a statistical aberration and investigators concluded that aflibercept and ranibizumab produced similar vision gains. When data from HARBOR,⁶ CATT,⁷ IVAN⁸ and other comparative trials are also analysed, one concludes that antiVEGF monotherapy has hit a 'ceiling' with respect to vision improvement in AMD trials.

The phase 2 CLEAR-IT 2 trial showed that aflibercept possesses a prolonged duration of action (average time to reinjection: 129 days),⁴ which would allow treatment with fewer injections. This was consistent with mathematical modelling (based on aflibercept's binding affinity and expected intravitreal half-life) that predicted a duration of action of 2.5 months (compared to monthly ranibizumab).⁹ At first glance, the VIEW trials supported this extended duration of action as patients receiving aflibercept 2 mg q 8 weeks improved similarly to those receiving ranibizumab every 4 weeks (+8.4 letters vs +8.7 letters).⁵ For physicians who treat patients according to trialestablished protocols, this allows them to confidently extend the inter-treatment interval from 4 to 8 weeks without subjecting patients to poorer outcomes.

However, because ranibizumab was not tested at treatment intervals of longer than 4 weeks, we are unable to say that aflibercept lasts twice as long as ranibizumab. Some clues regarding the relative durations of action of these drugs can be gleaned from the year 2 data. During the second year of the VIEW trials, patients were evaluated monthly and treated as needed, but at intervals not exceeding 12 weeks. On average, patients receiving either aflibercept or ranibizumab lost an average of –0.8 letters. Patients receiving aflibercept required fewer injections than those getting ranibizumab (4.2 vs 4.7); additionally, 48% of patients getting aflibercept and 40% of those receiving ranibizumab received the minimum number (3) of injections.¹⁰ The 12 week 'cap' prevents us from calculating the mean and standard deviation of the intertreatment intervals for the cohorts but the numbers suggest that the median duration of aflibercept action was just over 3 months, not substantially different from predictions made by both the CLEAR-IT 2 and mathematical modelling. These data suggest that administering aflibercept either PRN or according to treatandextend will provide a longer duration of action than either ranibizumab or bevacizumab. More surprising was the performance of the ranibizumab group in year 2. These patients required fewer injections than those in both the CATT and IVAN trials but not many more than in the PIER trial,¹¹ in which patients who received quarterly injections lost vision.