Topical Delivery of Retinal Drugs

Is the “holy grail” of drug delivery in view?

ASHISH SHARMA, MD • FRANCESCO BANDELLO, MD, FEBO

Topical instillation of eyedrops constitutes the most common route of ophthalmic drug delivery. Drops penetrate inside the eye via three major pathways: trans-sclerally, transcorneally, and transconjunctivally.

Of these pathways, the transcorneal route, which forms the best part of drug transport, is limited by multiple factors, such as the corneal epithelial barrier, drug solution drainage, lacrimation, and tear dilution. These limitations create additional impediments to posterior-segment drug penetration, which is already hindered. However, there are other potential routes that could facilitate penetration, such as delivery via the pars plana and diffusion through the sclera.

Currently, among the most challenging aspects of designing efficient topical therapies is the discovery of ideal molecules that are sufficiently small and potent and that have charge features that are suitable for enhanced ocular penetrance.

Technological innovation has facilitated the advancement of newer methods of topical drug delivery, such as cyclodextrins, topical permeation-enhancing liposomes, and biodegradable microspheres that contain ocular pharmacologic agents and that make it possible to deliver drugs to the posterior segment. This article focuses on several promising topical drugs that are currently undergoing clinical trials.

SQUALAMINE (OHR-102)

Squalamine (under development by Ohr Pharmaceuticals [New York, NY]) is an antiangiogenic drug with a mechanism of action that includes uptake by endothelial cells and calmodulin binding and displacement.¹ The drug inhibits aberrant neovascularization through the inhibition of angiogenic factors, such as basic fibroblast growth factor, platelet-derived growth factor (PDGF), and VEGF.^2-4

The IMPACT (phase 2) trial, which will assess the safety and efficacy of topical squalamine in cases of wet age-related macular degeneration, has completed enrollment (Figure 1, page 56). At the nine-month analysis, combination therapy (squalamine eyedrops and ranibizumab [Lucentis, Genentech, South San Francisco, CA]) has demonstrated better results compared to ranibizumab monotherapy in terms of visual acuity (overall P=.025, classic lesions P=.007) (Figure 2, page 56).⁵

Figure 1. IMPACT Study design.

Figure 2. Interim data show 65% additional gain in visual acuity in case of combination of OHR-102 and ranibizumab compared to ranibizumab combined with placebo.

In relation to use in retinal vein occlusion, 20 naïve patients were enrolled in a phase 2 clinical trial of topical squalamine eyedrops in cases of macular edema caused by retinal vein occlusion. Eight, three, and nine patients with branch, hemicentral, and nonischemic central RVO, respectively, were involved.

Initially two doses of ranibizumab were given, first at the second week and then at the sixth week. Squalamine therapy was continued for 10 weeks in all of the patients.

At week 10, the average ETDRS letter gains were +18.2, +18.1, and +32.3 in CRVO, BRVO, and HRVO patients, respectively. Furthermore, 80% of the cases showed gains of ≥3 lines. Overall, the mean Snellen VA achieved was 20/32 in all of the groups at the end of week 10. Central foveal thickness improved to 270 µm from 723 µm. Only one patient required a rescue injection of ranibizumab at the end of week 10.

An extension arm of this study randomized patients in a 1:1 ratio at week 10. Recently, results of this phase 2 study demonstrated that patients who were on combination therapy (ranibizumab PRN + 0.2% squalamine lactate ophthalmic solution) achieved better visual gains than patients receiving monotherapy (ranibizumab PRN). There was a meaningful difference of a 4.5-letter gain in the combination arm at the end of 38 weeks of follow-up, compared to monotherapy.⁶

To understand the efficacy, a phase 3 trial has been designed that will assess the role of combination therapy (squalamine eyedrops plus ranibizumab) vs ranibizumab monotherapy in subjects with wet AMD. This is a nine-month trial, but it will be followed up for two years for safety analysis. The patients will be randomized 1:1 during the first year. One arm will receive ranibizumab monthly injection plus squalamine eyedrops two times per day, and the other arm will receive ranibizumab monthly injection plus placebo.

In the second year, one arm will receive ranibizumab PRN plus squalamine twice per day, and the other arm will receive ranibizumab PRN plus placebo two times per day.⁷ The proportion of patients achieving VA gains of 3 or more lines will be the primary endpoint.

MC-1101

Choroidal blood flow has been etiologically linked to AMD by many authors. MC-1101, developed by MacuCLEAR (Plano, TX), has a positive impact on modulating choroidal blood flow (Figure 3). It was hypothesized that this impact could be a potential treatment modality for dry AMD.⁸

Figure 3. Proof of concept data from MacuCLEAR, Inc., showing increase in choroidal blood flow with the use of MC-1101.

In a recent phase Ib/proof of concept clinical trial, MacuCLEAR demonstrated the safety and tolerability of MC-1101. Laser Doppler experiments proved that MC-1101 could penetrate to the retina. Moreover, it demonstrated biological changes to the choroidal blood flow.⁸ MacuCLEAR has collaborated with Mystic Pharmaceuticals (Austin, TX), which produces the VersiDoser technology that helps to avoid unnecessary flooding of the drug.⁹

Recruitment for the phase 2/3 trial of MC-1101 1.0% BID in the management of dry AMD over two years is under way, with an intended enrollment of 60 patients and with results expected in April 2016.¹⁰

PAN-90806

PanOptica (Bernardsville, NJ) has developed PAN-90806, which is an inhibitor of VEGF. In an animal model (neonatal mice) of laser-induced choroidal neovascularization, which represents neovascular AMD, PAN-90806 demonstrated the ability to reduce lesion size compared to controls. Similarly, in another neonatal mouse model representing diabetic retinopathy, PAN-90806 could demonstrate reduction in preretinal neovascularization, compared to controls.¹¹

Currently 50 patients are being enrolled for a phase 1 safety and tolerability study of PAN-90806 in cases of neovascular AMD, with an estimated primary completion date in September 2015.¹²

OT-551

OT-551 (Othera Pharmaceuticals, Kennett Square, PA) is a compound with higher penetrability in the cornea because of its small lipophilic molecular size, followed by conversion to piperidine. In vitro data have shown that, TEMPOL-H, which is a hydroxylamine of the 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (of which OT-551 is a metabolite), can rescue retinal pigment epithelial cells from oxidative insult and photoreceptors from acute light-induced insult.^13,14

An initial phase 2 study of 10 patients with bilateral geographic atrophy have demonstrated that OT-551 is a well-tolerated drug apart from minor adverse effects. Two-year data showed a mean change in BCVA of +0.2±13.3 letters in study eyes, with fellow eyes showing a change of -11.3±7.6 letters (P=.0259).¹⁵

Conversely, the OMEGA study, a two-year, multicenter, phase 2 clinical trial of OT-551 was terminated after 18 months due to its failure to show meaningful effects in the prevention of GA in AMD cases.¹⁶

PAZOPANIB

Pazopanib (Votrient) is an anti-VEGF agent developed primarily for neovascular AMD by GlaxoSmithKline (Philadelphia, PA). It blocks the tyrosine kinase receptors, including PDGFR, VEGF 1, 2, and 3, c-Kit, and fibroblast growth factor receptor 1 (Figure 4).

Figure 4. Pazopanib causes blockage of tyrosine kinase receptor mediated biochemical signaling cascade.

It seems there are differences across animal species because pazopanib was found to be effective in mice, but it failed to show beneficial effects in a rabbit model of CNV.¹⁷ These data suggest that the blood-retinal barrier (BRB) of mice and rabbits are different, and it also provides the insight that outer BRB penetrance could be the key factor for topically used drugs to demonstrate their effects on the retina.

Although the phase 1 results with pazopanib were encouraging, ¹⁸ a phase 2 clinical trial in patients with neovascular AMD was ended due to lack of efficiency in an initial analysis.

ATG003

ATG003, a compound developed by CoMentis, Inc. (South San Francisco, CA), is a proprietary ophthalmic formulation of mecamylamine. It inhibits the endothelial nicotinic acetylcholine receptors and decreases angiogenesis and vascular permeability (Figure 5, page 57). The drug received FDA approval as an antihypertensive drug, along with a drug that works as a smoking-cessation aid.

Figure 5. ATG003 inhibits endothelial nicotinic acetylcholine receptors and decreases angiogenesis.
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After a phase 1 trial, two phase 2 trials of ATG003 (topical mecamylamine) — a placebo-controlled, randomized safety and efficacy trial in patients receiving maintenance intravitreal injections of either ranibizumab or bevacizumab (Avastin, Genentech); and a safety and tolerability study in patients with diabetic macular edema were completed.¹⁹ Results from both of the above-mentioned studies are not yet available.

TG100801

TargeGen’s (San Diego, CA) molecule TG100801, a prodrug that penetrates the eye and is converted to its active drug TG100572, belongs to the category of tyrosine kinase inhibitors. Its interferes with kinases related to the VEGF pathway, and it suppresses VEGF activation of endothelial cells much earlier in the cascade and blocks the effects of VEGF on the receptors by blocking the enzyme.

In in vitro experiments, TG100801 has demonstrated that it can induce apoptosis of proliferating endothelial cells, which are potentially related to formation of new vessels. Moreover, the drug reduced endotoxin-induced nitric oxide release, demonstrating its potential anti-inflammatory role.²⁰

Although the initial phase 1 results announced in 2007 indicated good tolerability of twice daily dosing in healthy subjects, a phase 2 study in patients with AMD that commenced in 2007 was terminated for unknown reasons.²¹

REGORAFENIB (BAY 73-4506)

Regorafenib (Stivarga, Bayer, Whippany, NJ) is an inhibitor of multiple kinases, including PDGF β, VEGF 1, 2, and 3, TIE2, oncogenic kinases, and fibroblast growth factor, which are predominantly implicated in oncogenesis and neovascularization (Figure 6).²²

Figure 6. Regorafenib is a multikinase inhibitor that targets kinases, including VEGF which is involved in angiogenesis.
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Onder et al showed that topical administration of regorafenib 1 mg/mL was helpful in prevention of alkali-induced corneal neovascularization in rats.²³ In treatment-naïve participants with wet AMD, the DREAM phase 2 trial of topical regorafenib is under way, and completion is expected by May 2016.²⁴

TOPICAL DEXAMETHASONE-CYCLODEXTRIN MICROPARTICLE EYEDROPS

Cyclodextrin microparticles, when mixed with tear fluid, form a water-soluble drug/cyclodextrin complex. In a rabbit model, topical microparticulate 1.5% (wt/vol) dexamethasone/γ-cyclodextrin demonstrated delivery of drug to the vitreous humor and retina.^25,26

Tanito et al showed that topical microparticulate 1.5% was well tolerated and caused reduction in patients with DME with improvement in vision.²⁷ A phase 2/3 study comparing the results with this eyedrop to intravitreal bevacizumab with and without macular laser was initiated in March 2012, but the present recruitment status is unknown.²⁸

FOV 2304

FOV 2304 (Fovea Pharmaceuticals, Paris, France) is an inhibitor of bradykinin B1 receptor. It was designed for treatment of DME. Its topical form makes it a simple and noninvasive therapy (Figure 7). Two doses of this drug underwent a six-month phase 2 safety and efficacy study in subjects with center-involving DME. The study has already been completed, but the results are not yet known.²⁹

Figure 7. FOV 2304 inhibits bradykinin B1 receptor leading to reduced inflammation and angiogenesis.
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RECOMBINANT HUMAN NERVE GROWTH FACTOR

The role of recombinant human nerve growth factor (rhNGF; Dompe Farmaceutici S.p.A, Milan, Italy) is currently under investigation for typical retinitis pigmentosa (RP). A phase 2b/2 trial is under way that is evaluating the safety and efficacy of rhNGF in patients with typical RP. The trial has 50 subjects with a follow-up of 24 weeks, and a topical solution is being compared with vehicle. The expected completion date is November 2015.³⁰

TOPICAL INTERFERON GAMMA-1B

Topical interferon gamma-1b interferes with JAK-STAT and mTOR signaling in the RPE. A pilot phase 1/2 study of this compound for the treatment of classic central serous chorioretinopathy has been completed. Another pilot phase 1/2 study evaluating its role in macular edema/intraretinal schisis, as well as cysts in rod-cone dystrophy and enhanced S-cone syndrome, is currently in the process of recruiting patients. A phase 1 trial evaluating the role of topical interferon gamma-1b in cases of uveitic macular edema has also been completed. The results of all of these trials are awaited.³¹

LHA510

Alcon (Fort Worth, TX) has developed a molecule, LHA510, which is under investigation for AMD. To analyze the safety of single and multiple dosing of LHA510 in patients of AMD, a randomized, double-masked, vehicle-controlled study that was a first-in-human trial was performed. To explore the role of LHA510 eyedrops as a maintenance therapy, another proof of concept study is under way and recruiting patients. This study has an likely finishing point in March 2016.³²

MTP-131

MTP-131 (Stealth Peptides Inc., Newton, MA) is an innovative molecule that selectively binds and protects cardiolipin from peroxidation, thereby reducing glucose- and peroxide-induced oxidative stress and improving the overall survival of endothelial cells. A phase 1/2 study in patients with DME and AMD is under way, which is a single-center dose escalation study.³³

UFO-21

Unoprostone isopropyl (UFO-21) is under investigation for RP. A phase 3 clinical multicenter study is being performed in Japan, with continuous administration and a comparative study arm. It is a placebo-controlled, double-masked study in patients with RP, which is evaluating the effects of 0.15% UFO-21 eyedrops on improvement in central retinal sensitivity with Humphrey field analysis over a 52-week period. A safety study will be performed over 52-week continuous period in patients who complete the comparative study period. The study is under way but not recruiting subjects at this point.³⁴

LATANOPROST

A phase 4, randomized, double-blind, two-year intervention study comparing topical application of latanoprost (Xalatan, Pfizer, New York, NY) with placebo eyedrops in subjects with diabetic retinopathy has been completed recently, and the results are awaited.³⁵

PROPANOLOL

A phase 2 study of propranolol eyedrops in preterm newborns with a precocious stage of retinopathy of prematurity (ROP) has been planned, with an expected recruitment of 55 patients and completion in November 2015.³⁶

Propranolol eyedrop treatment will be given to preterm newborns with stage 2 ROP (zone II without plus) until retinal vascularization is completed. During the first three days of treatment and at the stable state, propranolol concentrations will be calculated on dry blood spots. Monitoring of cardiovascular and respiratory parameters will be performed with periodic blood sampling to evaluate the metabolic, renal, and liver functions for safety analysis. Sequential ophthalmological observation will be undertaken to monitor treatment effectiveness, ROP progression, and possible complications.

LOTEPREDNOL ETABONATE

Kala Pharmaceuticals (Waltham, MA) has invented a nanotechnology-based approach to explore the immense potential of topical corticosteroids in the management of DME. A phase 2 clinical trial for the treatment of DME is analyzing topical loteprednol etabonate dosed in a mucus-penetrating particle QID.³⁷

OC-10X

OC-10X (OcuCure Therapeutics, Roanoke, VA) is a selective tubulin inhibitor belonging to the quinazolinone group. The potential development of this drug is to target PDR and AMD. It is highly lipid soluble and has an extremely low molecular weight of 300 Da, enabling it to achieve therapeutic concentrations at the retina-choroid.

When drug was administered once every hour over four hours, the drug reached a corneal level of 100% and a lens/vitreous level of 11%. It also reached to the sclera-choroid-retina at a level of 83% in rats.

As a topical agent, OC-10X has shown both angiolytic (regression) and antiangiogenic (inhibition) characteristics in animal models of AMD. OC-10X demonstrates the efficacy of a vascular targeting agent without the traditional toxicity as shown by other agents. The ocular and systemic safety and tolerability of OC-10X has been investigated in a phase 1 trial, but results are currently unavailable.³⁸

CONCLUSION

Frequent intravitreal injections of anti-VEGF compounds form the current standard of care for the management of retinal disorders. There is a need for therapies that lessen the treatment load and that have a potential to improve VA in a larger proportion of patients. There is a considerable effort in this direction to explore topical drug options that can reach the site of pathology and reduce the treatment burden in the form of either monotherapy or combination therapy.

In this article, topical therapies that have reached human trials were included. There are many other molecules that have shown promising results in animal experiments, which could be conceivable candidates in the ever-expanding list of potential topical pharmacotherapeutic armamentarium for human use. RP

REFERENCES