Super dose ranibizumab

[caption id='attachment_593' align='alignright' width='400' caption='Image 1: An 86-year-old man presented with a history of blurred and distorted vision for six months due to a subfoveal vascularised PED, left eye. BCVA was RE: 20/30, LE: 20/100'][/caption]

Although anti-VEGF therapy with intravitreal ranibizumab (Lucentis, Genentech) is a major advance in the treatment of exudative age-related macular degeneration (AMD), many eyes on monthly treatment continue to have persistent disease activity. At one year in the Comparison of Age-Related Macular Degeneration Treatments Trial (CATT), 50 per cent of eyes treated with monthly ranibizumab 0.5mg had persistent fluid on OCT. In addition, vascularised pigment epithelial detachment (vPED), which is present in about seven per cent of eyes with neovascular AMD and is a poor prognostic factor in natural history studies, has responded incompletely or inconsistently to conventional doses of anti-VEGF agents.

At the annual meeting of the Association for Research in Vision and Ophthalmology, results reported from investigator-initiated, prospective studies suggest a potential role for a 2.0mg 'super dose' ranibizumab regimen in these challenging cases.

Eric Chen MD, a retinal specialist at Retina Consultants of Houston, Houston, Texas, reported interim findings from the Phase 1-2 Superdose AntiVEGF for recalcitrant AMD (SAVE) study. All patients received ranibizumab 2.0mg/0.5 cc monthly x 3 doses and were then randomised to follow-up every four or six weeks with 'capped PRN' therapy in which ranibizumab 2.0mg is injected mandatorily every three months or earlier if there is clinical or imaging evidence of CNV membrane activity. Patients were eligible for the study if they had persistent fluid on OCT after receiving at least nine ranibizumab injections within the past 12 months and Snellen equivalent BCVA between 20/25 and 20/320.

[caption id='attachment_594' align='alignright' width='400' caption='Image 2: Within four weeks after a single injection of a super-dose of 2.0mg/0.05ml of ranibizumab (Genentech, Inc. South San Francisco, CA), there was flattening of the PED besides resolution of the subretinal fluid, LE'][/caption]

The two-year study is planning to enroll 90 eyes. Dr Chen reported one-year data from the first 50 eyes that on average had received almost 27 prior ranibizumab injections, including more than 10 within the past year; the mean time between the previous injection and screening/day zero treatment was 36 days. Mean baseline ETDRS BCVA was 68.8 letters (Snellen equivalent about 20/44), and mean retinal central subfield thickness was 414 microns.

Most patients received retreatment at all scheduled follow-up visits during the capped PRN phase. OCT imaging at one week after the first 2.0mg injection showed retinal thickness decreased in a significant proportion of patients and by a mean of 53.3 microns. There was some mild regression of the effect thereafter, but a mean reduction from baseline of 30 to 40 microns was maintained at one year.

BCVA also improved early and improved further over time. By eight weeks, patients in the four- and six-week follow-up groups had mean gains of almost five and three letters, respectively, and at one year their BCVA had improved 4.9 and 3.7 letters from baseline. There was one patient who developed a subretinal hemorrhage after his month three injection, which could not definitely be attributed to the higher dosage medication.

'The rationale for using a higher dose in these incomplete responders derives from pivotal clinical studies showing better outcomes using ranibizumab 0.5mg versus 0.3mg. The gains in BCVA are impressive, considering that these eyes had already been treated aggressively with ranibizumab so that they had good BCVA on entry,' commented Dr Chen.

'Based on these interim results, we think super dose treatment has some benefit for incomplete responders, although it is not a solution for everyone. Whether or not treatment frequency can be reduced with super dose treatment is a question yet to be answered, but the fact that vision improved over time in our patients followed every six weeks suggests it may be possible,' he said.

He added that the data also provide good scientific rationale for the Phase 3 HARBOR study that is comparing ranibizumab 0.5 and 2.0mg administered monthly or PRN in eyes with treatment-naïve exudative AMD, although results may differ given the different study populations.

Flattening vPED

Clement Chan MD, FACS, a retinal specialist in private practice, Palm Springs, CA, reported results of a one-year, multicentre, randomised, open-label study with four arms comparing intravitreal ranibizumab 2.0mg and 0.5mg administered monthly or PRN for the treatment of vPED associated with neovascular AMD. The PRN dosing groups initially received four monthly injections.

Between 2008 and 2010, the study enrolled 27 eyes of 27 patients with submacular vPED ≤12 disc area in size, ETDRS BCVA ≥19 and ≤69 letters, and submacular haemorrhage or fibrosis <50 per cent of the entire PED. Mean follow-up was nine months with a range of three to 12 months. There were no clinically relevant differences between groups in baseline characteristics, and number of injections administered was similar in all groups after adjustment for differences in follow-up duration.

Mean BCVA improved from 55.8 to 63.7 letters, and the vision change did achieve statistical significance. There were no differences in any functional or anatomic outcomes comparing the monthly and PRN regimens, and analyses with patients stratified by dose showed both ranibizumab 0.5 and 2.0mg significantly decreased central 1.0mm thickness, subretinal fluid, and mean height, surface area and greatest linear diameter of the vPED. CME decreased significantly only in the 0.5mg group, but the 2.0mg dose was significantly more effective than 0.5mg in reducing subretinal fluid and vPED dimensions earlier in the study (Week-4 to 8) as well as for consistently flattening vPED. Early significant BCVA improvement (Week-4) was also found only with the ranibizumab 2.0mg dose.

'Our outcomes are consistent with the interim results reported last year from the vPED study showing ranibizumab 0.5mg resolved subretinal fluid, haemorrhage, and exudates, but did not flatten the vPED, and the substantial overall improvement in BCVA in our study was driven primarily by the benefit of the 2mg dose,' Dr Chan said.

'However, an RPE tear developed in three eyes in our study, each in a different treatment group, and further study is needed with both doses to investigate this safety issue.'

In both SAVE and the vPED study, there were no unexpected ocular adverse events and no serious systemic adverse events associated with ranibizumab 2.0mg.