Glaucoma Clinical Research: Trends in Treatment Strategies and Drug Development

Abstract

Purpose: To investigate the trends and progresses in glaucoma research by searching two major clinical trial registries; clinicaltrials.gov, and Australianclinicaltrials.gov.au. Methods: All clinical trials with glaucoma covered by Clinicaltrials.gov, and Australianclinicaltrials.gov.au starting the study before 1 January 2021 were included. Trials evaluating glaucoma treatment were separated from non-treatment trials and divided into three major categories: "laser treatment," "surgical treatment," and "medical treatment." In the category of "medical treatment," new compounds and their individual targets were identified and subcategorized according to treatment strategy; intraocular pressure (IOP)-lowering, neuroprotective or vascular. The phase transition success rates were calculated. Results: One-thousand five hundred and thirty-seven trials were identified. Sixty-three percent (n = 971) evaluated glaucoma treatment, of which medical treatment accounted for the largest proportion (53%). The majority of medical trials evaluated IOP-lowering compounds, while trials with neuroprotective or vascular compounds accounted for only 5 and 3%, respectively. Eighty-eight new compounds were identified. Phase I, II, and III transition success rates were 63, 26, and 47%, respectively. Conclusion: The number of clinical trials in glaucoma research has increased significantly over the last 30 years. Among the most recently evaluated compounds, all three main treatment strategies were represented, but clinical trials in neuroprotection and vascular modalities are still sparse. In addition to traditional medicines, dietary supplements and growth factors are assessed for a potential anti-glaucomatous effect. Phase II and III success rates were below previously reported success rates for all diseases and ophthalmology in general. A stricter phenotyping of patients can improve the success rates in glaucoma and ophthalmological research and gain a better understanding of responders and non-responders.

Keywords: clinical trials; drug development; glaucoma; treatment; trends.

Figure 1

(A) Total number of registered glaucoma clinical trials (Phase I–IV) over time. Each study was categorized as treatment or non-treatment. The number of clinical trials increased dramatically from 2000–2004 to 2005–2009, peaking in 2010–2014 and declining in 2025–2019. Of important note, the last column contains only trials from 2020, while the other columns cover a period of at least 4 years. (B) Total number of registered clinical trials in the treatment group divided into medical treatment, laser treatment or surgical treatment. Medical treatments constitute the majority of the assessed glaucoma treatments except from 2020, where surgery was the most frequently evaluated treatment in glaucoma trials.

Figure 2

New compounds represented in all included trials. Each compound is categorized as IOP-lowering (light green), vascular (orange) or neuroprotective (dark green). The compound is linked to its target. The targets are listed to the right and visualize how some compounds act on several targets. For example: (1) Trabodenoson is an IOP-lowering compound that targets adenosine receptor A1; (2) Clonidine is a vascular compound targeting six different alpha-adrenergic receptors (1A, 1B, 1D, 2A, 2B, and 2C); (3) Insulin is a neuroprotective compound that acts on insulin receptor, insulin-like growth factor 1 receptor, retinoblastoma-associated protein, and carboxypeptidase E.

Figure 3

New compounds classified as supplements, stimulants, or transplant identified in all included trials. Each compound is categorized as IOP-lowering (light green), vascular (orange), or neuroprotective (dark green). The compound is linked to its target. The targets are listed to the right and visualize how some compounds act on several targets. For example, forskolin is an IOP-lowering compound that targets adenylate cyclase type 2, G(s) subunit alpha-isoforms short, and adenylate cyclase type 5. Only one group of vascular compounds, namely antioxidants, that act on free radicals, is represented.

Figure 4

New compounds in ongoing trials, trials completed within 2 years and compounds resulting in recently approved glaucoma treatment drugs. The compounds are linked to the target family listed on the right site. The three colors indicate whether a compound is categorized as neuroprotective (dark green), vascular (orange), or IOP-lowering (light green). For example: (1) Omidenepag Isopropyl, a prostaglandin analog, has been approved and works by lowering IOP; (2) ANX007 is a neuroprotective monoclonal antibody c1q and trials with this compound have been completed; (3) Sildenafil is a phosphodiesterase inhibitor that acts on the microvascular blood flow and trials are still ongoing.

Figure 5

Clinical development success rates. Clinical trial phases are linked to study purpose; phase I studies investigate safety and dosage, phase II studies investigate efficacy and side effects, phase III studies investigate efficacy and monitoring of adverse events, and phase IV studies investigate post-approval surveillance. Before entering phase IV, an FDA review is required. The percentage of drugs that proceed to next phase is listed. Success rates from Table 3 are listed as “Glaucoma” and compared with success rates for ophthalmology and for all indications in the period 2011–2021 in general. Source: BIO (Biotechnology, Innovation, Organization) (47).