Barriers to IOP-independent treatments in glaucoma clinical trials

Glaucoma represents a group of diseases associated with progressive loss of the retinal ganglion cells (RGC), degeneration of the optic nerve, and loss of the visual field (VF). Besides its devastating effect on patients’ vision and quality of life (QoL), glaucoma also exerts a huge economic burden, with estimates of costs up to 2511 USD per person and per year, depending on the disease stage [1].

Currently, all therapies approved for glaucoma treatment are based upon intraocular pressure (IOP) lowering only. As the IOP is the most important risk factor in all types of glaucoma, this seems a logical and evidence-based approach [2, 3]. Nevertheless, glaucoma progresses silently, with only 10–50% of all patients being aware of having the disease until late [4]. Treating everyone with ocular hypertension (OHT) could be a way to reduce the number of glaucoma cases. Nevertheless, the conversion rate from OHT to glaucoma is quite low [3]. In addition to this limitation, one should also consider the costs and side effects of IOP-lowering treatments. Moreover, glaucoma management is, usually, individual to each patient and, therefore, very difficult to standardise.

Eye drops are known to be associated with poor compliance, mainly due to side effects, difficulty with drop administration and, in some cases, to the costs. Even when therapies require only once-a-day administration of the drug, with an increase in compliance, progression still occurs due to either suboptimal IOP control over 24-hours or to additional risk factors, including poor ocular perfusion that can further exacerbate progression of the disease [5]. Consequently, attempts are made to improve compliance and effectiveness by developing various interventions, from sustained release delivery systems (Durysta, Allergan), to intracameral implants (iDose, Glaukos), drug-coated contact lenses (Mediprint), and even first-line selective laser trabeculoplasy (SLT) or micro-invasive glaucoma surgeries (MIGS) [6]. However, each of these techniques have also their disadvantages, from being limited to one injection per patient (Durysta), to the need of having more data on the long-term IOP-lowering effectiveness (MIGS).

It is without doubt that lowering IOP removes some of the stress that results in neurodegeneration. However, it does not stimulate RGC survival or resilience [7]. Indeed, glaucoma is a multifactorial disorder with other risk factors involved, besides an abnormal IOP, many of those very likely to be involved in RGC loss in glaucoma, acting on various pathways.

There are many IOP-independent antiglaucoma agents that have been tested in research settings, of which some are presented in Table 1. Yet, none of them is currently approved by regulatory authorities to treat glaucoma.

Table 1.

IOP-independent antiglaucoma agents.

Medication	Description and mechanism of action
Memantine	•Non-competitive N-methyl-D-aspartate (NMDA) inhibitor •Protection against RGC loss in animal models [17]
Nicotinamide	•Nicotinamide adenine dinucleotide (NAD) precursor; REDOX cofactor •Retinal ganglion cell neuroprotection through prevention of metabolic disruption from ocular hypertension [18]
Brimonidine	•α-2 adrenergic agonist •Lowers IOP •IOP-independent neuroprotective effect via the modulation of glutamate-induced toxicity [19, 20]
Ginko Biloba	•Antioxidant function via stabilisation of the mitochondria that have entered the apoptotic pathway •Increases blood flow, reduces free radical damage, and interferes with glutamate signalling [21]
Coenzyme Q10 (CoQ10) with Vitamin E	•Mitochondrial targeted antioxidant •Protects against glutamate excitotoxicity •Topical CoQ10 prevented retinal ganglion cell apoptosis and loss as assessed in vivo by Detecting Apoptotic Retinal Cells (DARC) in an animal glaucoma model [22]
Citicoline	•Intermediate in the membrane phospholipids •Has shown neuroprotective effects in neurodegenerative diseases, brain trauma, amblyopia, and glaucoma [23, 24]
Ciliary neurotrophic factor (CNTF)	•Neurotrophic factor able to induce neuronal cell differentiation and neurite outgrowth and protect cells from neurodegeneration [25]
Platelet-derived growth factor (PDGF)	•Stimulates astrocytes and amacrine cells to secrete factors protecting ganglion cells [26]
Mesenchymal stromal cells (MSC)	•Stem cell therapy •Neuroprotective and promote regeneration in an animal glaucoma model and after optic nerve injury, mediated by their immunomodulatory and secretory properties, production of numerous cytokines, and growth factors [27]
Antiepileptic dugs: Phenytoin and valproic acid	•Improve RGC survival •Oral valproate improves visual acuity in advanced glaucoma patients, but without improvement in the VF or ERG [28] •Phenytoin improves VF in glaucoma patients
Gene therapy	•Correct a specific, well defined genetic defect or deliver protective factors using different pathways to stimulate survival and regeneration of RGCs using recombinant adeno-associated viral vectors (AAVs) [29]

Among those, neuroprotective treatments could, in theory, offer a better or a complementary alternative to IOP-dependent treatments. Indeed, the existence of a window period between the injury and the actual onset of the RGC death, allows such treatments to be effective, if applied early [8]. However, most glaucoma patients have experienced significant structural and functional loss by the time of diagnosis [8, 9]. In addition, the approved endpoints aimed at neuroprotection require long trials, with a large sample size and are, thus, very costly. It has been proposed that using trend-based VF progression endpoints or by combining OCT and VF endpoints, the sample size requirements in glaucoma clinical trials could be reduced [10]. Moreover, the use of artificial intelligence (AI)-based approaches is proving to be of a tremendous help in glaucoma diagnosis and follow-up [11, 12].

The future success of neurodegenerative therapies will also depend on perfecting techniques, such as Adaptive Optics (AO)-enhanced confocal scanning laser ophthalmoscopy (cSLO) or detection of Apoptosing Retinal Cells (DARC) technology, which has already been gone through Phase 1 and 2 clinical trials and claims to offer an early, pre-perimetric indication of glaucoma severity [13, 14].

Conclusion

Despite plenty of evidence supporting that factors other than IOP play a major role on glaucoma onset and progression, there are currently no IOP-independent therapies approved by regulatory agencies, mainly due to lack of endpoints that could be employed in short-duration trials. Glaucoma patients could also suffer from systemic disorders associated with either neurodegeneration (Alzheimer’s or Parkinson’s disease) or abnormal circulation (cardiovascular disease) that can act as confounding factors either on their own or due to the concomitant medications necessary to treat these diseases [15]. This variability could account for the fact that many novel drugs, despite showing promising results in animal studies, fail in clinical trials [16]. Glaucoma may be, indeed, a too complex disease for the currently available approved endpoints for evaluating the efficacy of new treatments, even when they are combined to form one single outcome measure. A multidisciplinary approach might be necessary to improve the current abilities of early diagnosis and efficient treatment of this disease.

Author contributions

DG: literature research, drafting, and proofreading the article. GM: drafting and proofreading the article.

Competing interests

The authors declare no competing interests.