complement inhibition

# Introduction Glaucoma is a common eye disease that damages **retinal ganglion cells (RGCs)** – the nerve cells that carry visual signals from the eye to the brain – leading to irreversible vision loss. Most treatments focus on lowering eye pressure (intraocular pressure or **IOP**), which indeed slows damage in many patients ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7512103/#:~:text=While%20sustained%20reduction%20of%20intraocular,that%20are%20able%20to%20confer)). However, a large fraction of glaucoma patients lose vision even when their IOP is normal or well-controlled. This has sparked great interest in **IOP-independent neuroprotection** – therapies aimed directly at keeping RGCs alive by targeting other stressors. Long-term RGC damage in glaucoma has been linked not only to pressure, but also to poor blood flow, excess excitation by brain chemicals (excitotoxicity), and **oxidative stress** (damaging molecules in cells) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7512103/#:~:text=While%20sustained%20reduction%20of%20intraocular,that%20are%20able%20to%20confer)). New treatments in development are striving to protect RGCs through several strategies: stabilizing cell mitochondria (the RGC “power plants”), supplying neurotrophic factors (growth signals), dialing down inflammation, and calming overactive immune cells (microglia). Below we review key late-stage candidates in these categories, explain their mechanisms and trial progress, and discuss how modern trial designs and biomarkers may finally yield success after past disappointments. ## Mitochondrial Stabilizers RGCs have very high energy needs. Mitochondria within RGCs produce ATP (energy) but can also generate harmful free radicals. Drugs or nutrients that **stabilize mitochondria** and boost healthy metabolism are a major focus. For example, **nicotinamide** (vitamin B3) is a precursor for NAD^+, a co-factor that fuels energy production. In glaucoma models, high-dose nicotinamide greatly protected RGCs ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9905873/#:~:text=The%20mitochondrial%20abnormalities%20that%20lead,related%20stress)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9905873/#:~:text=Williams%20et%20al,enzyme%20NMNAT1%2C%20were%20both%20reported)). This led to a large human trial: starting in 2022 the UK‐led study aims to enroll ~500 patients for 4 years to test whether nicotinamide delays vision loss ([www.ucl.ac.uk](https://www.ucl.ac.uk/news/2022/feb/vitamin-b3-trialled-glaucoma-treatment#:~:text=The%20trial%20will%20eventually%20recruit,patients%20from%20progressive%20vision%20loss)). This trial will also measure mitochondrial “power” in blood cells and other biomarkers ([www.ucl.ac.uk](https://www.ucl.ac.uk/news/2022/feb/vitamin-b3-trialled-glaucoma-treatment#:~:text=The%20study%20will%20measure%20the,predict%20disease%20progression%20for%20glaucoma)). Early small trials o

The 2024–2025 Pipeline for IOP-Independent Neuroprotection in Glaucoma

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