NEW ORLEANS — In patients with age-related macular degeneration with geographic atrophy, the complement inhibitor lampalizumab reduces disease progression by 20% and by 44% in a biomarker-defined subset, according to results from the MAHALO study.
"MAHALO is the first study to demonstrate a positive treatment effect with a complement inhibitor in geographic atrophy," said lead investigator Carl Regillo, MD, from the Wills Eye Hospital in Philadelphia, Pennsylvania.
Genetic factors account for more than 50% of the risk for macular degeneration. Complement factor D is a rate-limiting enzyme inhibited by the monoclonal antibody lampalizumab. By inhibiting complement factor D, lampalizumab blocks activation of the alternative complement pathway while preserving the host-defense response, Dr. Regillo explained here at the American Academy of Ophthalmology (AAO) 2013 Annual Meeting.
First presented in September at the EURETINA Congress and reported by Medscape Medical News at the time, the phase 2 MAHALO study includes 129 patients with bilateral geographic atrophy secondary to macular degeneration.
At baseline, mean visual acuity was 48, with a median Snellen equivalent of 20/100. Mean total area of geographic atrophy was 3.41 disc area, and total area of geographic atrophy was 8.65 mm2.
Patients had not have received previous intravitreal treatment, retinal surgery, or other retinal therapeutic procedures in the study eye. Participants were randomly assigned to receive intravitreal injections of lampalizumab, 10 mg monthly; sham injections monthly; lampalizumab, 10 mg every other month; or sham injections every other month.
The primary endpoint was mean change in geographic atrophy area from baseline to month 18, assessed by fundus autofluorescence. The sham injection groups were pooled for analysis.
"A positive treatment effect was observed in the lampalizumab monthly injection group at month 18, beginning at month 6," Dr. Regillo reported.
At month 18, mean geographic atrophy area was reduced by 20.4% in the lampalizumab group compared with the pooled sham cohort (P < .2). The difference between the groups was evident by 6 months, he said.
The adjusted mean change in best corrected vision from baseline to month 18 did not differ between the groups, but this outcome measure was designed for safety assessment and not powered for significance. No safety concerns were observed, Dr. Regillo reported.
In an exploratory analysis, investigators evaluated the relationship between specific genetic polymorphisms and response to lampalizumab and found 2 biomarkers that could be useful in selecting patients for treatment.
Risk Alleles
The investigators chose risk alleles in 4 known complement gene loci, based on previous studies: complement factor H, C3, C2/CFB (joint single-nucleotide polymorphism [SNP] tag), and complement factor I.
"Virtually all patients tested positive for complement factor H and C2/CFB," Dr. Regillo said. This eliminated these risk alleles in terms of their potential as biomarkers.
In contrast, C3 was positive in 47% of patients and complement factor I was positive in 57%. "We did find the treatment response magnified in the subpopulation that was positive for the complement factor I biomarker," he reported.
Complement factor I is a negative regulator, primarily of the alternative complement pathway, and it works with factor H to deactivate C3b.
The differential treatment response was clear within the factor I genotype, as the positive patients in the pooled sham cohort had significantly more geographic atrophy progression than negative patients.
Factor I was not only a prognostic biomarker but a predictive one. In the lampalizumab treatment groups, positive patients experienced the greatest treatment effect, with a highly significant 44% reduction in the rate of disease progression with monthly injections (P < .005).
When the drug was administered every other month to positive patients, disease progression was decreased by 18% (P = .23).
No unexpected serious adverse events were detected in the MAHALO study. Serious adverse events occurred in 3 of 87 patients receiving lampalizumab and 1 sham control patient.
"Overall, the adverse event rate was low," Dr. Regillo said. "These were mostly related to the injection and were comparable to other injected drugs. Lampalizumab was found to have an acceptable safety profile."
No cases of endophthalmitis developed, and intraocular inflammation and pressure elevation rates were consistent with rates for these adverse events seen in patients receiving ranibizumab for wet macular degeneration, he said.
"The MAHALO results suggest that the complement factor I biomarker is both prognostic for geographic atrophy progression and predictive for lampalizumab treatment response," Dr. Regillo concluded.
"Our caveats to the biomarker results are that this is a small sample size, and the SNP function is unknown, but we feel the results represent a hypothesis that needs to be replicated in future trials," he added.
Pravin Dugel, MD, from Retinal Consultants of Arizona in Phoenix and the Doheny Eye Institute at the University of Southern California, Los Angeles, told Medscape Medical News, "The results of MAHALO are extremely encouraging. It's the first time we have seen a positive result with a complement inhibitor. Lampalizumab is the first drug to show light at the end of the tunnel."
He added, "What I believe will happen with lampalizumab, if the findings are confirmed in phase 3 testing, is patient selection." Dr. Dugel predicts that there will be a specific group of patients who will benefit most, based on this biomarker analysis. "But they will have to be injected on a monthly basis," he added, "so patients will need to be motivated perhaps by having high-risk disease. Ultimately, a better delivery system is the goal. Meanwhile, the results are exciting, but we have to balance this with the need to properly select patients."
Dr. Regillo has financial relationships with Genentech, GlaxoSmithKline, QLT Inc, and Regeneron. Dr. Dugel has worked with Abbott Medical Optics, Acucela, Alcon Laboratories, Alimera Sciences, Allergan, ArticDx, Digisight, Genentech, LUX, Macusight, Neovista, Ophthotech, Ora, Regeneron, and ThromGenics.
American Academy of Ophthalmology (AAO) 2013 Annual Meeting. Presented November 16, 2013.
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