New Drugs and Treatments
New topical medications – new treatment paradigms!
Dr. Makoto Aihara highlights the unmet-needs in first-line glaucoma medications, including local and systemic side effects. This has spurred the development of new glaucoma medications: ROCK inhibitors and Omidenepag isopropyl (OMDI), as well as new combination drugs.
Dr. Aihara explained that OMNI is a selective EP2 agonist which increases aqueous humour outflow via both uveoscleral and trabecular pathways. Studies have shown that its efficacy is similar to latanoprost and is enhanced in combination with timolol. Switching from FP-agonist prostaglandin analogues to OMNI can result in resolution of prostaglandin-associated periorbitopathy syndrome (PAPS) and deepening of upper eyelid sulcus (DUES). Hence, he would offer OMNI as a first-line glaucoma eyedrop for phakic eyes with glaucoma as it has less cosmetic side effects compared with FP agonist prostaglandin analogues.
Subsequently, Dr. Aihara introduced the ROCK inhibitors: Ripasudil and Netasudil. Both of these increase trabecular outflow and Netasurdil also reduces aqueous production. There are no systemic side effects associated with ROCK inhibitors. Conjunctival hyperaemia is the most common adverse drug reaction, and this is significantly reduced 2 hours after instillation of the eyedrop. The efficacy of Netasurdil has been seen to shown to be comparable to timolol. Ripasudil effectively lowers the intraocular pressure (IOP) one month after use, and its efficacy is further enhanced after 6 months.
Finally, Dr. Aihara discusses new combinations of glaucoma medications, such as combined ROCK inhibitor with FP agonist prostaglandin analogue. He concludes that such new combination glaucoma eyedrops would improve patient adherence.
Glaucoma Therapeutics: Advances and Challenges in Drug Delivery
Dr. Paul Singh emphasized that patient compliance with glaucoma eyedrops is poor, hence there is a clinical need for sustained release drug delivery implants. These include biodegradable intracameral implants, non-biodegradable intracameral implants and external biodegradable and nonbiodegradable implants.
Dr. Singh shared that the Bimatoprost sustained-release intracameral biodegradable implant (DURYSTA) was approved in US-FDA in 2020. It lowers IOP for at least 4 months, and can be inserted at the slit lamp for glaucoma patients with open angles and healthy corneas. Dr. Singh presented some videos illustrating tips and tricks for successful implant insertion. Unlike bimatoprost eyedrops, the implant is not associated with long-term conjunctival hyperaemia, but 5% of eyes develop iritis and endothelial cell loss may be a concern with multiple implants. Hence, the US-FDA has only approved the implantation of one bimatroprost sustained-release intracameral implant, and Dr Singh would consider this implant for any patient with compliance issues.
Other sustained release biodegradable implants are in various stages of clinical trials, including travoprost biodegradable and nonbiodegradable implants, and external implants (punctal plugs, TODDDTM implant under the eyelid and the bimatoprost ring).
Dr. Singh concluded that sustained-release drug delivery implants can be used throughout the entire glaucoma treatment paradigm, for the whole spectrum of glaucoma patients from those with early glaucoma to those who suffer from advanced disease.
Neuroprotection and regeneration in glaucoma: Is it possible?
Dr. Jeffrey Goldberg explains that there is an opportune window between axonal damage and apoptosis of retinal ganglion cells, when interventions can be implemented to promote retinal ganglion cell survival, neuroprotection and axon or dendrite regeneration. There is an unmet need in glaucoma to provide better treatments beyond intraocular pressure (IOP), targeted at neuroprotection, regeneration and neuroenhancement. With increased understanding of glaucoma pathophysiology, potential candidates for clinical intervention are revealed.
Dr. Goldberg believes that improved trial designs to reduce the trial duration, with better patient selection and new exploratory biomarkers are required for neuroprotection trials to be feasible and affordable. Using these approaches, there are a number of trials in various stages of progress, including nerve growth factor (topical), anti-C1q intravitreal injection for glaucoma, ciliary neurotrophic factor and virtual reality based visual stimulation. Current real-world data on neuroprotection in glaucoma shows that brimonidine conferred more visual field protection compared with timolol in the LoGTS trial, although it is unclear what mechanisms are involved. Topical ROCK inhibitors has been shown to promote retinal ganglion cell survival and optic nerve regeneration in rodent studies.
Dr. Goldberg concludes that neurotrophic factors, rho-kinase inhibition and other strong candidates are ready for clinical studies in glaucoma patients, and merging therapeutic testing with biomarker exploratory endpoints to cross-validation will give us particular power as we launch these trials.
Non-IOP lowering treatments for glaucoma
Dr. Keith Martin highlights that glaucoma pathogenesis is complex and multifactorial, and there are many factors besides IOP which affect glaucoma progression. Hence, blindness from glaucoma still occurs despite effective treatments to lower IOP, with glaucoma progressing in some patients despite very low IOP.
He believes that when IOP reduction is insufficient, other potential therapeutic strategies should be explored. Nicotinamide (vitamin B3) is a modulator of mitochondrial function which has been shown to prevent glaucoma in mouse models, and also improves inner retinal function in glaucoma patients. A larger human clinical trial is currently underway to investigate whether nicotinamide should be combined with IOP-lowering medications as a supplement. Exercise has also been shown to improve the recovery of retinal ganglion cell function after pressure-induced injury in aged mice.
Dr. Martin raises two pertinent questions: How do we know if a non-IOP lowering therapy works in human patients? And do drugs that lower IOP by a similar amount always reduce visual field progression to the same degree? To answer these questions, neuroprotection trials would need to be more affordable to be feasible. Ideally, they should have a manageable number of patients with <18 months duration, with optimal use of visual field endpoints and better clinical trial design to evaluate a clinically meaningful neuroprotective effect. Lastly, Dr. Martin believes that there may be a role for neuroprotective gene therapy for glaucoma, especially to stimulate regeneration and to achieve cell reprogramming. Such therapies are currently in development and may offer hope for the future.
