MAHALO TRIAL

Monthly injections of the biologic agent lampalizumab (Roche) can significantly reduce the rate of progression of geographic atrophy (GA), according to the results of the MAHALO phase II trial, which Frank Holz MD presented at the 13th EURETINA Congress in Hamburg. “The results of MAHALO phase II study with a complement inhibitor are promising. It is the first study to demonstrate a positive treatment effect in geographic atrophy due to age-related macular degeneration, said Dr Holz, University of Bonn, Germany.

In the multicentre study, 123 patients with GA were randomised to receive injections of 10.0mg of lampalizumab or sham injections in one eye, either monthly or every other month. At 18 months’ follow-up, the mean amount by which the area of GA had increased from baseline values was 20.4 per cent lower in eyes receiving the monthly lampalizumab regimen compared to eyes in the sham injection groups. All of the patients in the study had bilateral GA secondary to AMD and were free of choroidal neovascularisation at baseline.

None of the study eyes had undergone previous intravitreal injections, had a history of retinal surgery or other retinal therapeutic procedures. The treatment groups were well-matched in terms of demographics and disease severity. The mean total area of atrophy in study eyes was roughly 3.4 disc areas or approximately 8.6mm2. In no cases was the total area of atrophy greater than five disc areas or less than one disc area. In addition, hyperautofluorescence was present adjacent to the GA at baseline in all eyes.

Effect evident from six months

The researchers tracked the changes in the atrophic area throughout follow-up using fundus autofluorescence imaging with a confocal SLO system. Their findings showed that the reduction in growth rate among the monthly lampalizumab group was evident from six months' follow-up until the end of the trial. However, the atrophic lesion growth rate in the group receiving lampalizumab every two months was virtually identical to that of the sham injection groups throughout the same follow-up period, Dr Holz pointed out.

In terms of visual acuity, there was no significant difference between the groups at any point of follow-up, indicating that the treatment did not have any deleterious effect on retinal function, he noted. The lampalizumab injections were well tolerated, overall, Dr Holz said. The most common of ocular adverse effects were eye pain and conjunctival haemorrhage, which were associated with the injection procedure and occurred with a frequency similar to that in eyes undergoing anti- VEGF injections. There were no serious adverse ocular events that could be related to the biologic agent and there were no serious systemic side effects and there were no deaths.

Some 30 patients dropped out of the study for various reasons. Treatment was discontinued in six eyes due to choroidal neovascularisation, which makes measurements of the atrophy very difficult. The most common cause for discontinuation was the decision of the patient or physician or because of a patient’s condition requiring another treatment.

Results varied between subgroups

One potentially very useful finding of the study was that there were certain subgroups of patients who did markedly better than others. In particular, the MAHALO study researchers found that among patients with certain exploratory biomarkers, the amount of GA progression among those receiving monthly injections of lampalizumab rate was 44 per cent lower than it was among those receiving sham injections.

In addition, among patients who were positive for the exploratory biomarkers and who presented with a visual acuity from 20/50 to 20/100, the growth of the GA was reduced by 54 per cent (p<0.005) among those receiving monthly lampalizumab. Dr Holz noted that 57 per cent of patients were positive for the exploratory biomarkers.

Damping down the alternative complement pathway

Lampalizumab is an antigen-binding fragment (Fab) of a humanised, monoclonal antibody that is active against complement factor D, a rate-limiting enzyme involved in the activation of the alternative complement pathway. The aim of treatment with the agent is to inhibit the alternative complement pathway.

Research has implicated hyperactivity of the complement pathway in the pathogenesis of AMD and geographic atrophy, Dr Holz explained. Moreover, many studies have shown that there are polymorphisms in the genes for proteins involved in the complement pathway that are strongly associated with the risk of AMD.

“What we have learned from various studies including the FAM and the AREDS study is that atrophy will continue to grow once it gets started. And so, although we don’t expect improvement of vision, it makes sense to try and slow down the growth of the atrophy. And if the phase II results are reproduced in the phase III trial and we find that we can preserve the foveal function over several years, that will be of high clinical relevance to patients,” he added.