|Year : 2017 | Volume
| Issue : 2 | Page : 134-139
Newer drugs in glaucoma management
Sujatha V Kadambi, Ronnie George
Smt. Jadhavbai Nathmal Singhvi Glaucoma Services, Sankara Nethralaya, Chennai, Tamil Nadu, India
|Date of Web Publication||26-Dec-2017|
Dr. Sujatha V Kadambi
Smt. Jadhavbai Nathmal Singhvi Glaucoma Services, Sankara Nethralaya, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Glaucoma, a chronic progressive neurodegenerative disease, has both intraocular pressure dependent and independent pathogenetic mechanisms. Medical therapy is the first line of treatment in glaucoma management. Patient adherence and persistence to pharmacotherapy is a great barrier to its success. This review highlights the recent advances in medical management and discusses newer pharmacotherapy including new molecules with novel mechanisms of action, novel target molecules/genes/tissues, and newer drug delivery systems, many of which are still in clinical trial phase.
Keywords: Glaucoma, Rho kinase inhibitor, gene therapy
|How to cite this article:|
Kadambi SV, George R. Newer drugs in glaucoma management. TNOA J Ophthalmic Sci Res 2017;55:134-9
| Introduction|| |
Glaucoma, a multifactorial neurodegenerative disease, is characterized by accelerated death of retinal ganglion cells (RGC) and their axons. It is a leading cause of irreversible blindness and the second leading cause of blindness worldwide. A systematic review and meta-analysis of population-based studies by Tham et al. have projected the global glaucoma burden to be 76.0 million in 2020 and 111.8 million in 2040, largely affecting people in Asia and Africa. Currently, the only known modifiable risk factor for glaucoma is intraocular pressure (IOP). Hence, it forms the mainstay target in contemporary glaucoma practice. IOP reduction is considered as the primary efficacy endpoint in majority of the glaucoma clinical trials in the present day scenario. Current regulation for a drug to be approved by the United States Food and Drug Administration (USFDA) is a comparable IOP-lowering efficacy and benefit-to-hazard ratio with respect to benchmark drugs. Structural changes in sync with clinically relevant functional change have now been included as endpoints in trials, especially for those involving neuroprotective glaucoma therapies.
A key element which is a barrier in the health-seeking behavior of patients and causes for failure of treatment is adherence and persistence to medical therapy. This is largely due to complex multiple drug regimen, side effects on long-term use and poor tolerability profile, difficulty administering drops due to essential tremors and lack of dexterity, lack of health education, inability to comprehend nature of disease, financial constraints, and travel issues.
Hence, the current research aims at the development of new drug formulations which have improved efficacy and duration of action, decreasing the need for multiple medications, thereby decreasing side effect profile and improving adherence and overall quality of life.
| Topical Medications|| |
Rho-associated coiled-coil-forming protein kinase (ROCK) inhibitors
The Rho family consists of guanosine triphosphate-binding protein which plays a vital role in regulating cell shape, motility, contractility, proliferation, and apoptosis. Rho-associated coiled-coil-forming protein kinase (ROCK) is serine/threonine inhibitors which act as selective inhibitors of the actin cytoskeleton contractile tone of smooth muscle in the trabecular meshwork. This results in increased aqueous outflow directly through the conventional pathway, thereby lowering IOP. There are also animal studies indicating that ROCK inhibitors may improve optic nerve head blood supply, increase ganglion cell survival, and reduce scarring, serving in bleb modulation in glaucoma surgery.
Ripasudil (K-115, Kowa Ltd, Nagoya, Japan) is the first Rho kinase inhibitor which has been approved in Japan for ocular hypertension (OHT) and glaucoma therapy. Nearly 0.4% of drug is to be used as a twice-daily application. Results from a Phase II clinical trial showed that the drug reduced IOP by 3.2, 2.7, and 3.1 mmHg from a baseline of 23 mmHg when used in concentrations of 0.1%, 0.2%, and 0.4%, respectively. The drug displayed a favorable safety profile, and 50% of enrolled patients had only mild conjunctival hyperemia in Phase I and II of the trial.,
Netasurdil (AR 13324) (Aerie Pharmaceuticals, North Carolina, USA) has a dual action of being a ROCK inhibitor and norepinephrine transporter inhibitor. It facilitates uveoscleral outflow in addition to the trabecular outflow and decreases the episcleral venous pressure. Roclatan, fixed-dose combinations of netasurdil with latanoprost 0.005% for once daily night dosing, is in Phase III clinical trial.
Although ROCK inhibitors seem very promising in the preliminary trials, many candidates have failed previously, as their selective inhibitory action is highly dose dependent. At higher concentrations, they tend to show unintended cross-reactivity with other protein kinase pathways, resulting in multitude of systemic side effects.
Adenosine receptor agonists
Many physiological and biochemical pathways in the body are mediated through G protein-coupled adenosine receptors. Adenosine receptor agonists stimulate secretion of matrix metalloproteinases (MMPs) in the endothelial cells lining the trabecular meshwork. This causes cell volume shrinkage and extracellular matrix remodeling, which ultimately facilitates conventional aqueous outflow. Trabodenoson (INO 8875) (Inotek Pharmaceuticals, USA) is an adenosine A1 receptor agonist currently in Phase III clinical trial. Phase II trials demonstrated a median IOP reduction of −6.5 mmg ± 2.5 (standard deviation) mmHg at 500 mcg dose by day 28 of trial. It demonstrated a favorable safety profile including an unremarkable electrocardiogram and the conjunctival hyperemias produced were generally mild and transient.
Can-Fite Biopharma (CF-101) is an adenosine receptor A3 agonist. When administered orally, in Phase II dry eye trial, a coincidental IOP reduction of 1.1 mmHg at week 12 was noted. This stimulated the idea for potential use of the drug for IOP-lowering therapy. The safety and efficacy of orally administered CF-101 in patients with elevated IOP and primary open-angle glaucoma (POAG) is currently in Phase II trial stage.
Prostanoid receptor agonists
Prostaglandin analogs, latanoprost and travoprost, act on prostanoid prostaglandin F receptor (FP receptor), a receptor for Prostaglandin F2 alpha (PGF2α). Bimatoprost is a synthetic PGF2α ethanolamide mimetic, termed prostamide F2α. These drugs enhance aqueous outflow through the uveoscleral pathway and cause IOP lowering. Recently, EP2, EP3 receptors have emerged as new targets of interest for IOP-lowering therapy.
DE-117 (Santen Pharmaceutical, Japan) is an EP2 agonist. These agonists cause relaxation of endothelial cells in the Schlemm's canal, facilitating uveoscleral outflow. They also increase conventional outflow by acting on the trabecular meshwork, decreasing cell contractility and collagen deposition  (Vis-a-vis latanoprost which increases trabecular meshwork contractility but decreases collagen deposition)
Taprenepag isopropyl (PF-04217329) is an EP2 agonist. Escalating topical doses of 0.0025% to 0.02% as once daily administration in patients diagnosed with POAG or OHT was compared with latanoprost 0.005%. Furthermore, unfixed combinations of the agonist with latanoprost were compared with latanoprost monotherapy in a 28-day trial. Results from Phase II showed that taprenepag was comparable to latanoprost 0.005% in IOP reduction. Preclinical animal studies demonstrated a dose-related iritis and increased corneal thickness with 0.015% and higher concentrations that resolved within 28 days of discontinuing the drug 
ONO-9054 (Ono Pharmaceuticals, Japan) has dual action of being an EP3 agonist and FP receptor agonist. IOP-lowering effect of a single topical administration of 0.3, 3, and 30 mcg/ml of ONO-9054 was studied in normotensive monkeys. Peak action was observed at 12 h. IOP reduction at 1 week was greater than that seen with latanoprost and travoprost (7.3 ± 0.8 mmHg vs. 4.9 ± 0.4 mmHg vs. 5.1 ± 0.6 mmHg). A randomized crossover study comparing AM and PM regimes with respect to IOP reduction in POAG and OHT found mean IOP reduction of 28.6% versus 31.0% for morning versus evening dosing. PM dosing was associated with slightly increased frequency of mild hyperemia and moderate dryness. When ONO 9054 (0.003%, 30 mcg/ml) was compared with Xalatan (latanoprost 0.005%, Pfizer, 50 mcg/ml), the odds of achieving a 35% IOP reduction was 4.85 times more for ONO 9054 compared to Xalatan.
Bamosiran (SYL040012) (Sylentis, Spain) is a naked double-stranded small-interfering RNA. It acts through specific gene silencing and causes beta-2 adrenergic receptor blockade, thereby decreasing aqueous production by the ciliary body. After topical administration, the drug is rapidly distributed in the anterior chamber. It is preferentially taken up by the ciliary body cells; hence, undesirable beta-receptor blockade in bronchioles and alveoli is limited. Studies wherein the drug has been administered as a single dose or multiple divided doses of 600 mcg/ml/day, over 1-week period, with the contralateral eye serving as control, have demonstrated a favorable safety profile. Phase IIb of a clinical trial which compared escalating concentrations of Bamosiran (0.375%–1.5%) qd with 0.5% timolol bd, found 1.125% Bamosiran to be non-inferior to timolol 0.5%, in patients with a baseline IOP >25 mmHg.
| Preservative-Free, Newer Preservatives, and Self-Preserved Iop-Lowering Medications|| |
Glaucoma patients have a high prevalence of ocular surface diseases. These have known to impact the quality of life and adherence to IOP-lowering medication. Many of these symptoms can be drug induced or due to the commonly used preservative benzalkonium chloride (BAK). BAK has been shown to exacerbate ocular surface conditions such as Meibomian gland More Details dysfunction, chronic conjunctival inflammation, keratitis, and causes tear film instability. As it is a dose-dependent toxicity, reducing the frequency of instillations, the use of fixed-dose combinations, can help improve tolerance. As per pharmacopeia recommendations, it is mandatory to have a preservative for microbial static or cidal action, once bottle is opened. Hence, the need for newer, less toxic preservatives.
Purite is a stabilized oxychloro complex (SOC). It is a mixture of chlorine dioxide, chlorite, and chlorate. On exposure to light, nascent chlorine radicals are produced which oxidizes glutathione and inhibits protein synthesis in microbial cells. It has a broad-spectrum antimicrobial activity even at low concentrations (0.005%). Studies have shown that decreasing brimonidine concentration from 0.2% to 0.15% and replacing BAK with SOC improve drug tolerance, especially in irritated eyes.
Polyquad (Polyquaternium-1) is a detergent-type preservative derived from BAK used for preserving some prostaglandin analogs (Travatan, Travoprost 0.004%, Alcon labs) and some tear substitutes. While it has been shown to be better tolerated than BAK, it does have some proinflammatory and cytotoxic effects on corneal epithelial cells.
SofZia is an ionic buffer composed of boric acid, propylene glycol, sorbitol, and zinc chloride. It has been introduced as an alternative to BAK (0.015%) in some formulations of travoprost (Travatan Z, Alcon laboratories, Texas). SofZia causes oxidative damage and bacterial cell death as these cells lack enzymes, catalase and cytochrome oxidase. When the preservative comes into contact with cations in tear film, it is rendered inactive and is thereby less toxic to the corneal and conjunctival epithelial cells. SofZia satisfied the US Pharmacopeia standards and is USFDA approved. However, it did not satisfy the European Pharmacopoeia standards of producing a complete reduction in bacterial colony count by 1 week and requisite 2 logs of fungus reduction during the 28-day test. It also showed limited effectiveness against Staphylococcus aureus.
One approach to eliminate the effect of these preservatives is to completely exclude them from the formulations, but that raises concerns with respect to contamination in multidose bottles. Preservative-free formulations of different beta-blockers, pilocarpine, and fixed combination of timolol, dorzolamide, and prostaglandin analog tafluprost have been introduced as single-dose units in different parts of the globe. However, single-dose units are less cost effective and have an increased risk of contamination.
| Neuroprotection|| |
Evidence from clinical trials such as advanced glaucoma intervention study, collaborative normal tension glaucoma study, and collaborative initial glaucoma treatment study suggest that progression and RGC loss can occur despite IOP lowering. Thus emanates the need to find mechanisms and drugs that retard neuronal apoptosis and degeneration.
Current research and clinical trials in neuroprotection are faced with challenges in terms of choosing the right experimental design, choice of an appropriate endpoint, and data interpretation. The slow progressive nature of the disease, variable worsening rates in different patients, outcome measure variability (mostly functional testing), and the need to test the new agent in patients who already have their IOP lowered attribute to the obstacles which one faces while designing these trials. An optimum way to distinguish change attributable to IOP lowering and that due to neuroprotection also remains unclear. Discrepancy also exists between preclinical and clinical phase as many animal models do not exactly simulate disease pattern in humans, and in vivo variability of disease pattern widely surpasses in vitro variability.
Memantine is a selective N-methyl-d-aspartate receptor antagonist with a potential to prevent glutamate-induced excitotoxicity of RGCs. A randomized double-masked placebo-controlled clinical trial which was studying the neuroprotective effects of memantine failed to meet its primary endpoint ,
Low-pressure glaucoma treatment study was a randomized trial comparing the efficacy of 0.2% brimonidine tartrate with 0.5% timolol maleate in preserving visual function in patients with low-pressure glaucoma. A lower rate of visual field progression was seen with brimonidine-treated patients compared to those receiving timolol monotherapy, despite achieving a similar mean IOP reduction. This was attributed to neuroprotective effect of brimonidine.
| Novel Drug Delivery Systems|| |
Nanoparticle-based topical formulations
Nanoparticle on a scale 10–1000 nm serves as vehicles for drug delivery. They are bioinert, biodegradable, and mucoadhesive polymers which aid corneal penetration of the drug.In vivo studies of carbonic anhydrase inhibitors, brimonidine, pilocarpine, using this delivery system has shown better drug permeability and stability compared to their commercially available counterparts.
Contact lens-based drug delivery
Silicone hydrogel soft contact lenses loaded with nanoparticles containing timolol have been found to elute the drug for more than a month in animal models. The drug diffuses from the lens into the tear film, increasing the bioavailability potential by 50%, as against topical formulations with only 1%–5% bioavailability. One big drawback while using hydrogels is that the drug elutes very quickly from the highly hydrated polymer networks as most IOP-lowering medications are water soluble.
Ocular inserts are polymers filled with the drug, which are designed to be placed in the conjunctival cul-de-sac or in the puncta. Inserts are composed of matrix-based, biodegradable polymers such as chitosan. The drug is directly absorbed by the mucosal lining. These inserts have the advantage of providing a prolonged drug delivery directly to the target tissue, decreasing the systemic side effects.
A randomized control study compared the IOP-lowering efficacy of topical bimatoprost ocular insert to twice daily timolol in POAG and OHT patients treated for 6 months. The Bimatoprost Corneal ring (For Sight VISION 5, California, USA) consisted of 13 mg preservative-free drug mixed with silicone matrix, with polypropylene support rings of diameters ranging from 24 to 29 mm. These rings were placed in the conjunctival fornices. A total dose of 2.5 mg was eluted, rate varying from 35 mcg/day on day 0–6 mcg/day on day 180. A clinically relevant sustained IOP reduction of 4–6 mmHg was achieved with the insert group. However, daily application of timolol produced IOP reduction of 1.5 mmHg more than the insert. Comfort profile and tolerability were found to be similar to topical bimatoprost 0.003%. Biodistribution studies in animal models comparing 99 Tc-Bimatoprost topical formulation to bimatoprost-loaded ocular insert found that inserts lowered IOP for a month following a single application, compared to eye drops which were effective only with daily administration.
Travoprost punctal plug (OTX-TP, Ocular therapeutics, Massachusetts, USA) is a rod-shaped polyethylene glycol-based hydrogel punctum plug encapsulating the active drug. It is placed in the vertical portion of the superior or inferior canaliculus. Violet coloration helps in direct visualization of the plug A study investigating that its safety and efficacy in an Asian population found IOP reduction of 24% (day 10) and 15. 6% (day 30), respectively. Only one participant required plug removal on day 1 due to epiphora.
Bimatoprost sustained-release (SR) implants (Bimatoprost SR, Allergan, Irvine, USA) are biodegradable implants which help in sustained drug delivery over 4–6 months. It is administered intracamerally through a prefilled applicator. Six-month results from Phase I/II clinical trial which compared topical bimatoprost 0.003% to intracameral administration of 6, 10, and 15 mcg of the drug showed favorable results. Preclinical studies have shown lesser periocular skin discoloration, fat atrophy, and eyelash growth in eyes injected with bimatoprost SR.
Studies are needed to evaluate if this SR intracameral prostaglandin analog administration will increase the risk of endophthalmitis, uveitis, and cystoid macular edema.
Intravitreal brimonidine is in Phase II clinical trial stage for treatment in dry age-related macular degeneration patients.
| Gene Therapy in Glaucoma|| |
Advances in the comprehension of the genetic basis of glaucoma have provided scope for the use of targeted gene therapy. Both viral and nonviral vectors are used to deliver genes to target tissue of interest such as trabecular meshwork, ciliary epithelium, ciliary body, and RGC. Gene therapy can be used to delete, replace/inactivate an aberrant gene, or introduce a new gene which helps in targeted therapeutic protein expression.
Downregulation of MMP1 expression in the trabecular meshwork is postulated to play a role in the pathophysiology of steroid-induced OHT. Animal studies have shown that intracameral injection of adenovius carrying the recombinant MMP1 resulted in reversal of corticosteroid-induced OHT. Loss of cyclooxygenase (COX-2) in nonpigmented ciliary epithelial cells has been implicated in the pathophysiology of POAG. Animal studies have demonstrated that intracameral delivery of lentivirus vectors expressing COX-2 and FP resulted in transduction of trabecular meshwork and ciliary epithelium and ultimately IOP reduction.
Adeno-associated viral vectors (AAV) have been used to deliver antiapoptotic genes to the retina in rodent glaucoma models. Intravitreal injections of AAV expressing brain-derived neurotrophic factor have resulted in RGC survival for a month in rodent models with induced OHT. Better comprehension of the pathophysiology of glaucoma will help unravel novel targets for gene therapy.
| Conclusion|| |
Although a galore of promising options exists for the development in glaucoma medical therapy, they have variable efficacies and side effect profiles which the treating physician needs to discern carefully before considering them as feasible options. Newer drug delivery systems help obliviate some issues with adherence but need more physician monitoring and maintenance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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