Issue: May 10, 2016
May 03, 2016
13 min read

Sustained-release drug delivery products edge closer to fruition

Issue: May 10, 2016
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Eye drops and injections, when needed day after day or month after month, can take a toll. Patient compliance with therapy becomes a problem. Treatment becomes expensive. Receiving repeated injections in the eye is not high on the patient’s list of things to look forward to. For those patients who need long-term therapy to control their IOP, heal a persistent wound or restrict neovascular vessels, for example, sustained-release medicines and methods of delivery are being developed to ease this burden.

A handful of sustained-release drug delivery implants are already on the market. Retisert (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb), Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan) and Iluvien (fluocinolone acetonide implant 0.19 mg, Alimera Sciences) are FDA approved for retinal/vitreous disorders.

But more technologies are in the pipeline, including plugs, extraocular rings, nanoparticles, contact lenses, modified molecules, stem cells and encapsulated cell technology.

Barbara Wirostko, MD, is co-founder of Jade Therapeutics and now chief medical officer of EyeGate Pharma, which recently acquired Jade to further develop a topical therapy for corneal diseases based on a proprietary polymer composed of a cross-linked modified hyaluronic acid.

The trade-offs of duration of action of sustained-release agents should be considered, according to Richard A. Lewis, MD. For example, if duration of action is too long, patients may be lost to follow-up.

Image: Nale P, OSN

“That cross-linked hyaluronic acid can be made into a liquid gel or film. Currently, we have a phase 2 Small Business Innovation Research grant from the National Science Foundation for close to $1 million using a formulation of the polymer in a film, basically a small strip, to elute antibiotics. That has been moving along nicely,” Wirostko said.

Jade Therapeutics has a contract with the U.S. military to develop the polymer for corneal repair and regeneration, and for delivery of human growth hormone in cases of persistent, non-healing corneal defects, Wirostko said.

Research has also focused on using the gel in intravitreal injection, Wirostko said.

“As a topical, it basically elutes [drug] from the film or the gel, serving as a sustained-release polymer because, by being cross-linked, you can imagine that it forms a type of a web around the different drug or protein or whatever is being delivered,” she said.

Another company, BioTime, is collaborating with Jade Therapeutics in developing the polymer to deliver stem cells to other parts of the body, not the eye, she said.

“You can deliver it anywhere. The preclinical work has been throughout the whole body,” Wirostko said. “I think, more importantly, for ophthalmology, this polymer has shown the ability to deliver proteins and growth factors in monkeys with great tolerability as well as the ability to deliver the proteins over a month. The key thing with our polymer is that it has efficacy in the eye whether it’s used alone, basically as a wound protectant, and/or in combination with drugs or proteins.”

The polymer is in clinical trials in Europe for stem cell delivery in non-ophthalmic dermal indications, Wirostko said.

Drug-eluting contact lens

Glaucoma is the main focus of research related to drug-eluting contact lenses, according to Daniel S. Kohane, MD, PhD, who with Joseph B. Ciolino, MD, is developing a prototype contact lens that releases dexamethasone, latanoprost or other agents.

Daniel S. Kohane

“In contrast to particulate approaches that use microparticles, nanoparticles or liposomes to control the drug release from the contact lens, our macroscopic approach uses a very thin drug polymer film that is encapsulated within the periphery of the contact lens,” Ciolino said. “That drug polymer film helps modulate the release of the drug from the contact lens.”

Kohane said that a drug-eluting contact lens has certain advantages over punctal plugs and intraocular implants.


“One advantage is that it’s not an implant. It is a topical device,” he said. “Our view is that probably the best place to apply the drug is right over where you want it to work, which is in the anterior chamber. Moreover, if this device falls out, the patient would be aware of it and would replace it immediately.”

The drug-eluting lens can dispense almost any agent into the eye, Kohane said.

“In theory, this lens could deliver any drug that has to be applied to the eye, with the caveat that there are some drugs that just are not going to get into the eye unless they’re injected,” he said. “We’ve shown delivery of antibacterial and antifungal drugs. We’ve released latanoprost and dexamethasone. In theory, this lens could deliver most drugs and, in fact, combinations of drugs.”

Ciolino and Kohane have more data on the contact lens being used with latanoprost than with any other agent.

“A lot of our research in the past has been oriented toward latanoprost, but that being said, we are not yet 100% convinced that we know what the actual commercial lead product would be,” Kohane said. “Right now, we have looked at glaucoma the hardest and we have the most data for that. That does not necessarily mean that it is what we are going to end up working on first as a commercial proposition. The lens can be used with a number of drugs.”

Kohane and Ciolino published a study in Biomaterials in 2014 that showed that the drug-eluting contact lens could maintain therapeutic levels of latanoprost in the anterior chamber of rabbit eyes.

“We’ve demonstrated that we can release therapeutic levels of dexamethasone, which is a steroid, and latanoprost, which is a glaucoma medication,” Ciolino said.

“Contact lens drug delivery addresses the problem of compliance, particularly for glaucoma patients. The contact lens can be placed on the eye and would continuously release a medication for up to a week or longer,” he said.

Ciolino and Kohane have performed extensive preclinical testing and are preparing for human testing. They are seeking potential investors and business partners.

“We understand that if this product is going to benefit patients, it needs to be commercialized. Therefore, we’re building an executional team to help us commercialize the technology. We’re also starting to meet with investors and strategic industry partners to generate funding,” Ciolino said.

Ciolino and Kohane hold an international patent for the drug-eluting contact lens.

More technologies for glaucoma

Several implants for glaucoma treatment are at various stages of the research and development pipeline, according to Richard A. Lewis, MD, OSN Glaucoma Board Member.

Barbara Wirostko

“There are a lot of things happening, some of which are now intracameral, inside the eye, and some are external,” he said. Lewis is a practicing glaucoma specialist as well as chief medical officer for Aerie Pharmaceuticals.

Bimatoprost sustained release (SR, Allergan) is a biodegradable implant delivered intracamerally via a prefilled single-use applicator and releases drug slowly over 4 to 6 months.

“There’s some magic in the amount of time you want the compound to last in the eye,” Lewis said, noting that there is a tradeoff. If duration of action is too long, patients may be lost to follow-up. “There’s a fine line between having a drug last for a year or years and having it last for 6 months.”

Interim results of a phase 1/2 study of Bimatoprost SR presented at the 2016 American Glaucoma Society meeting in Fort Lauderdale, Fla., showed that the drug was well tolerated and compared well with topical bimatoprost in reducing IOP. Two phase 3 clinical trials are underway to compare Bimatoprost SR with sham or timolol in the treatment of open-angle glaucoma or ocular hypertension.


The device has been under study for more than 5 years, Lewis said.

Envisia Therapeutics is developing its proprietary, biodegradable PRINT particle technology to deliver travoprost into the eye. Research is ongoing on iterations of PRINT particle technology to deliver anti-inflammatory agents and other agents not disclosed by the manufacturer.

Bimatoprost SR and the PRINT particle technology are both “very promising” with “good initial data,” Lewis said. There is less concern now than in the past with regard to the need for an injection every 6 months, he said, now that the retina community has come to routinely give injections for macular degeneration.

ForSight Vision5 is developing a bimatoprost ring, a prostaglandin-loaded device that is inserted in the conjunctival cul-de-sac via an external approach and rests under the eyelids. Mid-term results of an open-label extension study of a phase 2 trial presented at the AGS meeting concluded that the insert could provide IOP reduction for up to 13 consecutive months in patients with open-angle glaucoma or ocular hypertension. The device is replaced every 6 months.

Mati Therapeutics and Ocular Therapeutix are developing plugs that deliver medication.

Mati’s Punctal Plug Drug Delivery System (PPDS) has entered clinical trials with latanoprost for glaucoma and olopatadine for allergy relief. An additional glaucoma agent is being prepared for clinical trials, and an NSAID has been tested in preclinical studies. Proof-of-concept studies have been conducted, and preclinical data have been collected on molecules for dry eye disease and an anti-inflammatory, according to Mati’s website.

“Mati has a good product,” Lewis said, adding that the niche for the plug has not been established. “Will it fit in better in glaucoma, or will it fit in better postoperative cataract? Perhaps you can use it as an antibiotic- and steroid-dispensing unit. It can go either way.”

Ocular Therapeutix’s OTX-TP plug is inserted noninvasively through the punctum and rests inside the canaliculus, delivering travoprost to the ocular surface for up to 90 days. A phase 2a clinical trial conducted in the U.S. showed that the plug compared well with topical travoprost in terms of IOP reduction over 3 months, according to the company’s website.

Other glaucoma implants in development include the iDose travoprost intraocular implant (Glaukos), GrayBug (Aerie Pharmaceuticals/GrayBug) and Eye-D in-office insertable platform for controlled release of latanoprost (ViSci/BioLight Life Sciences).

In January, the FDA allowed Glaukos to proceed with a phase 2 randomized trial to compare the iDose travoprost intraocular implant with topical timolol maleate ophthalmic solution. Preclinical data showed that the implant reduced mean IOP more than topical timolol, a company press release said.

GrayBug is a polymer-drug biomolecular conjugate for the treatment of wet age-related macular degeneration and other neovascular diseases. The technology allows sustained delivery into various regions of the eye while minimizing inflammation associated with controlled-release technologies, according to the company website.

In May 2014, Aerie and GrayBug entered a partnership and licensing agreement to collaborate on delivery technologies for Aerie’s treatment candidates such as Rhopressa (netarsudil ophthalmic solution 0.02%).

The Eye-D platform (VS-101) is currently undergoing a phase 1/2a clinical study in the U.S. Results are expected to be released in the third quarter of this year, according to the BioLight Life Sciences website.

In addition, PolyActiva is developing bioerodible implants to release latanoprost and/or timolol for glaucoma and levofloxacin or a dexamethasone bolus dose for endophthalmitis and post-cataract prophylaxis.

New retina implants

Neurotech Pharmaceuticals is developing Encapsulated Cell Therapy (ECT) for the treatment of idiopathic parafoveal macular telangiectasia in the MacTel Project and for the treatment of wet macular degeneration.

ECT, a first-in-class genetically engineered ocular implant that enables continuous delivery of single and combination therapeutics, is inserted into the vitreous through a single incision and sutured in place. The ECT platform is made from medical-grade plastics and comprises a semi-permeable exterior capsule and internal scaffolding, which allows controlled cell growth and continuous protein production within the cartridge, according to the Neurotech website.


The basis of the ECT platform is the customized NTC-200 cell line, a proprietary line derived from normal human retinal pigment epithelial cells. Cell lines derived from the NTC-200 line are able to secrete therapeutic agents such as antibodies, fusion proteins and growth factors, according to Neurotech.

“The original Neurotech was used for geographic atrophy and for retinitis pigmentosa,” David S. Boyer, MD, said. Boyer is a retina specialist practicing at Retina-Vitreous Associates Medical Group in Beverly Hills, Calif., which is a clinical trial study location for Neurotech’s ECT technology. “The retinal pigment epithelial cells were modified to produce derivatives that were supposed to save ganglion cells. Ciliary neurotrophic growth factor is still around, and it’s being used to see if it’s possible to treat patients with idiopathic parafoveal macular telangiectasia in the MacTel Project.”

ECT may be used to create other therapeutic agents, Boyer said.

“They can modify these cells to produce various proteins and they can produce two different drugs in these little cylinders, so you could add a PDGF with a pure anti-VEGF,” he said. “That technology is very encouraging because it’s reversible.”

Clearside Biomedical is developing suprachoroidal administration of CLS-TA, a proprietary formulation of triamcinolone acetonide, alone and combined with Eylea (aflibercept, Regeneron) and PDGF inhibitors for the treatment of macular edema associated with noninfectious uveitis and retinal vein occlusion. Clinical trials are in progress or in the planning stages with various formulations.

Several longer-acting drugs are in development for the treatment of AMD, such as Alcon’s RTH258 and Allergan’s DARPin, which targets VEGF and could add PDGF in treating wet AMD.

“They’re not available at this time but are in clinical trials,” Boyer said. “The other avenue of treatment is cell-based technologies where cells are injected under the retina that produce anti-VEGF or receptor blockers that may last for years. There are some liposomes that can release drugs for many months that are going to go into clinical trials.”

In November 2015, Genentech launched a phase 2 clinical trial of the ranibizumab port delivery system (RPDS) in patients with wet AMD. The LADDER study is evaluating the safety and efficacy of the RPDS for the sustained delivery of Lucentis (ranibizumab, Genentech) in the treatment of wet AMD.

“The RPDS was well tolerated, improved best corrected visual acuity and was comparable to monthly ranibizumab injections in a phase 1 study,” Boyer said.

Pending approval

An iteration of the Ocular Therapeutix plug, Dextenza (OTX-DP), which delivers a 4-week tapered dose of dexamethasone to the ocular surface, appears to be the technology that is closest to an FDA decision. Dextenza is in phase 3 trials for the treatment of postsurgical inflammation and pain, and the FDA has set a Prescription Drug User Fee Act target action date for July 24, according to a news release from the company. – by Matt Hasson


Disclosures: Boyer reports he has been a consultant for Alcon, Genentech, Neurotech Pharmaceuticals and Regeneron and an investigator for Clearside Biomedical. Ciolino and Kohane report no relevant financial disclosures. Lewis reports he is chief medical officer for Aerie and a consultant for Alcon and Allergan. Wirostko reports she is co-founder of Jade Therapeutics and chief medical officer of EyeGate Pharma.


What are the advantages vs. disadvantages of intravitreal injections in relation to drug-eluting implants for retinal indications?


Despite concerns, implants offer promise

Andrew P. Schachat

Sustained delivery implants are appealing. They offer convenience for patients and, more importantly, are likely to improve adherence and compliance. If there is a missed visit, the drug is still on board and being delivered. They are a logical next step to improving on current intravitreal drug regimens.

But there are some obvious concerns. Efficacy creep: Usually, a sustained-release drug will be compared to the on-label recipe. If the study design is a non-inferiority trial or an equivalence study with a relatively wide confidence interval, the new approach may not be quite as good but still meet criteria for non-inferiority or equivalence. Safety: If something is going wrong and you want to stop treatment (or switch drugs), this is harder if there is an active implant inside the eye to remove. Cost: Sustained-release options are likely to be costly; is the added cost worth it? It is possible that some sustained-release versions will be priced as to be cost-saving vs. standard on-label periodic injections. I hope so.

Will the sustained-release drug be the one I want to use? For all kinds of regulatory and business reasons, sustained-release aflibercept and ranibizumab are more likely to come on line than a sustained-release bevacizumab. If there is an efficacy benefit via improved adherence and compliance, missed visit problems and missed injections are avoided on the efficacy side of things. But it may be easier for patients to miss a visit for an eye pressure check.

Sustained-release drugs will help patients and reduce suffering. Effective, safe and cost-effective new options are welcome. I look forward to having more of these in my patient care armamentarium.

Andrew P. Schachat, MD, is vice chairman of the Cole Eye Institute, Cleveland Clinic. Disclosure: Schachat reports he is a full-time employee of the Cleveland Clinic, a part-time employee of the state of Ohio and a consultant for AnGes; receives royalties from Elsevier; and has a possible future interest in Easton Capital.


Implants tried, true but costly

Jay S. Duker

A syringe and small-bore needle represent an incredibly efficient system for the delivery of medications to the posterior segment of the eye in an office setting.

Drug-eluting implants for posterior segment disease come in several varieties including FDA-approved, slow-release, erodible preparations that are delivered in an office setting (eg, Ozurdex, Iluvien) or non-erodible devices implanted in the operating room (Retisert). In addition, there are several investigational devices in development that are surgically implanted transsclerally. Some of these devices have chambers that can be refilled periodically in the office transconjunctivally, while others contain human cells that are “programmed” to deliver specific proteins over a set length of time (Neurotech).

Current FDA-approved drug-eluting implants containing corticosteroids have the advantage of being fully tested with level 1 evidence, suggesting both efficacy and safety when compared with the off-label use of the needle/syringe delivery system. The obvious downside is the increased cost as well as the increased corticosteroid-related complications that occur with use of the long-term release devices.

Jay S. Duker, MD, is an OSN Retina/Vitreous Board Member. Disclosure: Duker reports he is a consultant for Allergan and Bausch + Lomb.