Aqueous humor biomarker based method of identifying hyperactive complement mediated Geographic Atrophy (GA) and response to lampalizumab

Geographic atrophy (GA) is an advanced form of age-related macular degeneration, an eye disease that causes progressive loss of central vision and affects millions of older adults worldwide. It is one of the leading causes of blindness and currently has very limited treatment options. Clinical trials have tested new medicines for this condition, but so far most have not shown clear benefits in slowing vision loss.

Two large clinical studies, called CHROMA and SPECTRI, tested a medicine called lampalizumab. Lampalizumab is given as an injection into the eye and was designed to block part of the body’s immune system known as the complement pathway, which can become overactive and damage the retina (the light-sensitive layer of tissue at the back of the eyeball. Light that comes through the eye's lens are focused on the retina and turned into images by the brain). Unfortunately, these studies did not show that lampalizumab slowed the progression of geographic atrophy overall. Later analyses looked at whether certain groups of patients—based on their genes or protein markers in eye fluid—might have responded better, but no clear subgroup was identified.

In our research, we will take a new approach. We will use a computer-based method (an algorithm) that looks at proteins in the clear fluid from the eye, called aqueous humor. These proteins can provide a picture of how active the complement system is in the eye. We will test whether our method can identify people whose complement system is “hyperactive” at the start of the study, whether treatment with lampalizumab successfully reduces this overactivity, and if people who start out "hyperactive" and for whom lampalizumab successfully reduces this overactivity experience a clinically significant benefit in terms of their disease progression.

To do this, we will request access to specific data from the CHROMA and SPECTRI trials:

• Proteomic data (a detailed profile of proteins in the eye fluid) at the start of the study and after six months, excluding lampalizumab drug levels.

• Clinical outcomes including the area of geographic atrophy, best corrected visual acuity (BCVA, a standard test of vision with glasses), and low-luminance visual acuity (LLVA, vision in low-light conditions) at the start of the study, six months, and twelve months.

By linking the protein profiles with the anatomic (e.g., the structure of the eye and retina) and vision outcomes, we will test whether patients who show a beneficial change in complement activity after lampalizumab treatment also have slower worsening of geographic atrophy. If this is true, it could provide an important step toward identifying which patients are most likely to benefit from therapies that target the complement system. This research may also help guide future drug development for geographic atrophy by showing how biological markers in the eye can be used to predict treatment response.