SPECIAL SECTION: PATIENT COMPLIANCE

A serious issue gets serious attention

Help — lots of it — could be en route via drug delivery devices.

By Karl Csaky, MD

Ocular drug delivery research has generated significant buzz for several reasons:

1. The eye is a unique, self-contained organ separated from the rest of the body. As such, focusing a device or technique to uniquely treat one of many ocular tissues without affecting the rest of the body is easily achievable.

2. The anatomy of the eye. Multiple easily accessible surfaces, such as the cornea and sclera and intraocular spaces, contain fluid compartments, such as the anterior chamber and vitreous, that are easily approached for placement of a long-acting device.

3. Many ocular diseases, such as glaucoma, dry eye, macular degeneration and diabetic retinopathy, require long-term treatment approaches.

Due to the growing number of patients dealing with chronic ocular diseases, business reports such as Citi GPS predict that the ocular delivery market could reach upwards of $29 billion by 2030.¹

Reason No. 4, and more

There is a reason No. 4: the numerous new ocular drug delivery methods under development, all with the singular goal to obviate patient-related drug compliance problems. Patient compliance is a significant issue, specifically affecting ocular inflammation, glaucoma, dry eye and ocular allergy, all of which require frequent topical medications. For example, studies demonstrate that only 25% of patients properly administer a topical ocular medication for glaucoma² while nearly 50% of glaucoma patients eventually become noncompliant and discontinue topical application of a medication within six months.³

Other issues that limit the efficacy of topical drug administration are the drug’s short residence time on the ocular surface, short duration of exposure within the ocular tear film of only two to three minutes and the rapid elimination of a significant portion of the drug via the tear duct.⁴ Ocular penetration studies demonstrate that topical administration results in bioavailability levels of only 1% to 5%.^5,6

Another significant source of topical drug clearance is the episcleral lymphatics. The episcleral tissues, including Tenon’s and the conjunctiva, contain a large number of lymphatics. These are very active in clearing ocular surface debris, bacteria and other material.⁷ These lymphatics also appear to be active in removing surface medications. Preclinical studies on animals have demonstrated that marker dye placed on the ocular surface appears within the submandibular lymph nodes within 30 minutes. Follow-up studies demonstrated that reducing the activity of these lymphatics in animals via conjunctival transections improved ocular drug penetration.⁸

Due to these issues, our patients need alternative delivery devices that can overcome many of the above issues that limit the use of topical medications. Sustained drug delivery or zero order release from a drug delivery device can improve drug tissue pharmacokinetics. For example, ocular tissue levels were significantly higher when cyclosporine was delivered from a sustained delivery device compared with topical administration.⁹

However, while ocular drug delivery appears to be in most cases a more desirable therapeutic route, this approach has several inherent limitations. One is the concept of drug payload. Depending on the ocular bioavailability and the duration of drug exposure, the drug delivery device needs to contain a certain amount of the drug. Given the size constraints and the low ocular bioavailability of an ocular delivery device, they may only be able to achieve therapeutic ocular levels for a few weeks to a few months.

Despite this concern, several ocular delivery systems are in clinical trials. Here is a summary of these systems divided into anatomic location of their placement.

Intracanalicular

This approach involves placement of a drug delivery device into either or both of the tear duct punctum. While the placement is considered noninvasive, several limitations of this approach need to be considered, in particular the device’s retention rate within the punctum. Blinking, lid squeezing and ocular movements can all dislodge a device from the punctum. Also, the device must not interfere with normal tear drainage.

Several approaches are under active investigation. These technologies appear very promising because of their wide range of disease targets and the minimally invasive nature of their placement.

Ocular Therapeutix is in clinical trials with bioerodible hydrogel encapsulating microspheres that swell upon insertion in the punctum. Several clinical trials are underway for a device-release dexamethasone (DEXTENZA) for ocular pain and inflammation, allergic conjunctivitis and inflammatory dry eye disease.

In a phase 2 study, DEXTENZA was superior over placebo for absence of anterior chamber cells (P<0.005) at days 14 and 30 and absence of pain at all time points (P<0.005) in patients after cataract extraction with IOL implantation. The device sustained 100% retention through day 14 and 97% through day 30; there were no long-term spikes in IOP. In addition, a recently completed phase 2b study of sustained travoprost from a similar punctal device demonstrated IOP lowering comparable with topical timolol for 75 days.

Mati Therapeutics is in clinical trials with a punctal plug delivery system (Evolute) releasing latanoprost for the treatment of glaucoma and releasing olopatadine for allergy relief. The proprietary design of the punctal implant has resulted in reported retention rate of 92% over 12 weeks. The company has completed multiple phase 2 clinical trials using the Evolute platform for glaucoma, ocular hypertension and allergy patients. These studies can be viewed at www.ClinicalTrials.gov.

Mati Therapeutics’ unique punctal-plug drug delivery device

Intracameral

This approach overcomes the challenge of the low ocular bioavailability of surface-applied medications by allowing a drug to release directly into the anterior chamber. This method may prove to be more efficacious than noninvasive approaches that place a device in the punctum or episcleral space. However, it is considered invasive and requires a special injector that can place the device within the small confines of the anterior chamber. Additional challenges include potential contact with the corneal endothelium and angle structures and hence possible toxicity issues. Several devices are under investigation.

Allergan is in clinical trials with a bioerodible device based on its Ozurdex platform. This device injects and releases bimatoprost into the anterior chamber for the treatment of glaucoma. Allergan reported six-month interim results from a 24-month phase 1/2 clinical trial of 75 patients who received one intracameral device at four-dose strengths in one eye (6, 10, 15 or 20 micrograms) and treated with daily topical bimatoprost 0.03% in the other eye. All dose strengths were comparable with bimatoprost through week 16 with a mean IOP lowering of 7.2 mmHg to 9.5 mmHg compared with a mean of 8.4 mmHg in the topical bimatoprost eye. A single intracameral placement of the device lowered IOP in 92% of subjects at four months and 71% of subjects at six months while demonstrating a favorable efficacy and safety profile.

Envisia Therapeutics uses a proprietary manufacturing procedure (PRINT technology) to develop bioerodible platforms for drug release. The company is studying an extended-release biodegradable travoprost formulation for six-month duration when placed into the anterior chamber. The company released interim analysis of a phase 2 trial in glaucoma patients demonstrating clinically meaningful reduction in IOP for the nine-month evaluation period following a single administration with effects comparable to daily prostaglandin analogs and 0.5% timolol maleate.

Icon Bioscience is in clinical trial with the Verisome platform, a liquid formulation delivery system injected into the anterior chamber designed to release its medications for up to nine months. At present, dexamethasone- (IBI-10090) and triamcinolone-releasing formulation are in various phases of clinical development for the treatment of postcataract surgery inflammation and DME and uveitis, respectively. Results have been reported of a 90-day prospective, randomized, double-masked, placebo-controlled, multicenter clinical trial phase 3 study of IBI-10090 at two doses, 342 µg and 517 µg, involving 394 patients undergoing cataract surgery posterior chamber IOL implantation. At both doses of IBI-10090, the percentage of patients with an anterior chamber cell (ACC) grade of 0 at day eight was statistically significant compared to placebo. Specifically, 63.1% in the 342 µg treatment group and 66% in the 517 µg treatment group (P< 0.001) demonstrated an ACC grade of 0 as compared to 25.0% in the placebo group. No eye-related, serious adverse events were reported up to day 90 and adverse events among the three groups were similar.

Episcleral

This approach involves the placement of a sustained delivery device under the conjunctiva. Considered minimally invasive with limited potential for side effects, this approach offers the advantages of better maintenance of drug levels due to avoidance of clearance by the tear film and the possibility of a large drug payload due to the possible large size of the implant. The major limitation at the present time is the close proximity to the episcleral lymphatics that appear to be extremely efficient at removing released drug from this space. Several devices are under investigation.

Envisia Therapeutics is also developing a bioerodible difluprednate-release subconjunctival device to treat post-cataract inflammation. It is based on a similar manufacturing strategy as described above (PRINT technology). The device is in preclinical development.

Anterior chamber injection of Verisome liquid.

Peregrine Ophthalmics is developing a latanoprost formulation within liposomes that injects into the subconjunctival space to treat glaucoma. The company reported data from a phase 2a clinical trial that demonstrated clinically significant ocular hypotensive effects six months after injection.

pSivida is developing a 3-mm bioerodible implant releasing latanoprost (Durasert) designed to be injected into the subconjunctival space for the treatment of glaucoma. The device is currently in phase 1/2 clinical trials.

ForSight Vision5 is studying the efficacy of the Helios insert ring, which releases bimatoprost for glaucoma. Placed noninvasively under the top and bottom lids, the device does not degrade and can be replaced every six months. The device is in phase 2 clinical studies.

Conclusion

The field of ocular drug delivery is extremely active, and a host of various devices placed in several ocular locations are in clinical trials for a wide range of ocular diseases. It is not a question of if but when such devices will become available in ophthalmology. Therefore, it is extremely likely that in the not-too-distant future our use of simple topical drops will only be for short-term indications, making longer duration topical medications a treatment of the past. OM

REFERENCES

About the Author
	Karl G. Csaky, MD, PhD, is the T. Boone Pickens director of the Clinical Center of Innovation for Macular Degeneration and managing and medical director of the Retina Foundation of the Southwest and a partner at Texas Retina Associates in Dallas, Texas. He has been involved in research to improve ocular drug delivery and clinical research in AMD.