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Phase II clinical study results indicate monthly lampalizumab therapy may be successful treatment
Dr. WilliamsBy Michelle Dalton, ELS; Reviewed by David F. Williams, MD, MBA
Edina, MN-A phase II study of a humanized monoclonal antibody fragment that binds factor D has shown a 20% reduction in slowing geographic atrophy (GA) progression over 18 months, according to David F. Williams, MD, MBA.
The MAHALO study of lampalizumab (formerly FCFD4514S, Genentech) also showed no unexpected or unmanageable serious adverse events, said Dr. Williams, who is a partner at VitreoRetinal Surgery, PA, Edina, MN, and an assistant clinical professor of ophthalmology, University of Minnesota, Minneapolis.
“The clinical implications of the phase II results, if confirmed in a future phase III trial, are profound,” Dr. Williams said. “It would represent a seminal moment in ophthalmology-the first time that complement inhibition would show a positive therapeutic effect in an ophthalmic disease.
“This would herald a new era of treatment for a major unmet need-slowing GA progression due to age-related macular degeneration (AMD) and preserving visual function for people with a previously untreatable disease,” he added.
Lampalizumab, also known as anti-factor D, is a selective inhibitor of the alternative complement pathway. It is a humanized monoclonal antibody fragment that binds factor D, a rate-limiting enzyme in the pathway, Dr. Williams said.
Lampalizumab “blocks activation of the complement system through the alternative pathway, while preserving the host-defense response through the classical and mannose-binding lectin pathways,” he said.
MAHALO was a phase II study that included a phase Ib multidose safety run-in.
The four-arm study enrolled 129 patients randomly assigned 1:2:1:2 into monthly sham (n = 21) and 10 mg lampalizumab (n = 43) arms, and every other month sham (n = 21) and 10 mg lampalizumab (n = 44) arms, with the main inclusion parameter bilateral GA secondary to AMD in the absence of choroidal neovascularization, with the GA between 1 and 7 disc areas with a presence of hyperautofluorescence.
If the GA was multifocal, at least one lesion had to be greater than one-half disc area, Dr. Williams said.
Baseline best-corrected visual acuity (BCVA) had to fall between 20/50 and 20/400. The investigators used fundus autofluorescence to assess the changes in GA area from baseline to month 18.
For the analyses, the sham arms were pooled to increase the precision of the estimate, he said.
“Secondary endpoints were mean change in GA area with color fundus photography and mean change in baseline BCVA, though phase II was not powered to assess secondary endpoints,” Dr. Williams said.
Additional analyses included segmenting the patients by baseline GA area to assess the effect of lesion size on area expansion over time.
At baseline, average visual acuity was about 20/100 with GA lesions averaging 3.4 disc areas (about 8.5 mm2).
At 18 months, the lampalizumab monthly arm had a 20.4% reduction in progression relative to the pooled sham arm. This difference was seen beginning at month 6, Dr. Williams said, and was statistically significant at each subsequent time point.
Though the study was not powered to assess the efficacy of the compound on vision, the mean change in BCVA over time was assessed for safety signals.
“There were no safety concerns with lampalizumab relative to the pooled sham arm,” he said.
“The [monthly lampalizumab] reduction was remarkable,” Dr. Williams said. “This is the first time any therapy has shown clinical trial evidence of efficacy in slowing GA progression.”
In a specific subpopulation of GA patients treated monthly with lampalizumab that were identified using exploratory biomarkers, the GA progression rate was decreased by 44% (p < 0.005) at 18 months.
In the subset of patients positive for the exploratory biomarkers who presented with better vision (20/50 to 20/100), progression of the GA area was reduced by 54% (p < 0.005) at 18 months when treated with monthly lampalizumab.
From the patient samples collected in the MAHALO study, 57% of patients were positive for the exploratory biomarkers.
“The next steps regarding a potential phase III study are still under consideration,” Dr. Williams said.
However, he said, more information on the biomarkers would be presented in the near future.
David F. Williams, MD, MBA
Dr. Williams is a member of Genentech’s advisory board.
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