Ines Lains, MD
Massachusetts Eye and Ear Infirmary
Dr. Jean-François Korobelnik, Professor of Ophthalmology and the Head of the Department of Ophthalmology at the University Hospital of Bordeaux in France, presented the results of the PULSAR trial – a phase 3 active-controlled trial assessing the efficacy and safety of high dose aflibercept (8 mg) in neovascular age-related macular degeneration (nAMD).
After the VIEW-1 and VIEW-2 trials demonstrated that aflibercept 2 mg at 8-week intervals was non-inferior to monthly ranibizumab, aflibercept has become widely used to treat nAMD. However, even at 2-month intervals, the burden of injections for clinicians, patients and the healthcare systems cannot be underestimated.
As explained by Dr. Korobelnik, the PULSAR trial aimed to assess if high dose aflibercept administered at longer intervals (12 and 16 weeks) was non-inferior to the standard 2 mg dose given every 8 weeks. This is based on the rationale that a higher dose of medication (8 mg concentrated in 70 microliters) may have a longer durability. The study included only patients with treatment-naïve nAMD, who were randomly assigned to three groups on a 1:1:1 ratio: (i) active comparator (2q8 group) – 3 monthly injections of aflibercept 2 mg, followed by injections every 8 weeks; (ii) high dose every 12 weeks group (8q12) – 3 initial monthly injections of aflibercept 8 mg followed by injections every 12 weeks; and (iii) high dose every 16 weeks group (8q16) – aflibercept 8mg monthly for 3 months followed by an injection every 16 weeks.
A total of 1,011 patients were randomized in multiple centers across the globe (223 sites in 26 countries), with 93% completing 48 weeks (1 year) of follow-up. The primary outcome was defined as change in BCVA at 1-year, with a non-inferiority margin of 4 ETDRS letters.
Dr. Korobelnik shared with excitement that this outcome was met both for the 8q12 and 8q16 groups (p= 0.0009 and 0.0011, respectively). Absolute BCVA at the same follow-up time was also statistically comparable among the three treatment groups. In terms of predefined anatomical outcomes, as one of the inclusion criteria was evidence of intraretinal or subretinal fluid affecting the central subfield on OCT, the proportion of patients without fluid in this area both at 16 and 48 weeks was also analyzed, and noted to be higher in both groups treated with aflibercept 8 mg.
Importantly, Dr. Korobelnik highlighted that in this first year of the study, for the high dose aflibercept groups, the protocol included shortening of dosing intervals up to a minimum of 8 weeks if there was evidence of disease progression. This was both based on visual acuity (loss of 5 letters of BCVA from week 12) and OCT pre-defined criteria (increase in more than 25 microns in central retinal thickness form week 12 or new onset of foveal neovascularization or foveal hemorrhage). Using these criteria, 83% of the patients treated with high dose aflibercept were maintained on at least q12 intervals.
Finally, Dr. Korobelnik also shared data on the safety profile of aflibercept 8 mg, reporting that in the PULSE trial both non-ocular and ocular adverse events were comparable among the high dose aflibercept groups and the standard 2 mg dose group. Despite the higher volume of medication injected, there were no differences in intraocular pressure among the three treatment groups. There were also no new safety concerns for aflibercept 8 mg and no cases of endophthalmitis or occlusive retinal vasculitis were observed.
In conclusion, Dr. Korobelnik highlighted that in the PULSE trial high dose aflibercept (8mg) enabled similar BCVA outcomes with less frequent injections than the standard 2 mg dose, while maintaining a similar safety profile.
The audience also had the opportunity to ask questions. Among them, one of the participants inquired whether during aflibercept pre-clinical studies the toxicity of the 8 mg dose had been assessed. It was clarified that the initial studies tested 2 and 4 mg and their efficacy and safety profile were similar, but that the 8 mg dose was not initially examined.