Are sustained-release drugs the answer to ophthalmology’s topical drop problem?
Alice T. Epitropoulos | | Longer Read
Ocular drugs are only as good as their delivery. The ideal delivery system is designed to enhance bioavailability, permeate ocular barriers, and provide controlled and sustained drug release – where the therapeutic is needed. Strides have been made in achieving these goals in both the anterior and posterior segments in recent years, and additional advances are being achieved with each new approval. Topical drops remain widely used, but these standard treatments can be challenging for many of our patients. Adherence to topical drop regimens, either for chronic treatment or in the postoperative setting, is known to be poor. Some of our patients have a real fear of putting drops in their eyes, while others may have physical limitations, such as poor dexterity or a tremor, that makes it difficult to properly instill the drops, particularly for post-surgical patients who may have limited experience with their use.
Indeed, a study by Jella An and colleagues demonstrated that more than 90 percent of post-cataract patients administer their eye drops incorrectly (1). Intraocular injections, on the other hand, are invasive, carry a risk of infection, and often require that patients return faithfully to the retina specialist’s office, month after month (2). In addition to adherence issues associated with complex eye drop regimens, there are important cost concerns that can be mitigated by reduced dependence on drops. As the cost of drops continues to increase (driven by higher co-pays and increasingly limited formularies), we often take this into consideration when we prescribe them. Sometimes the decision is taken out of the physician’s hands; for example, when branded drops are substituted with generics at the pharmacy.
Inherent treatment challenges
Suboptimal drug bioavailability with topical drops further reinforces adherence and cost issues and results from multiple barriers to drug entry, including nasolacrimal drainage, epithelial transport barriers, and clearance from the vasculature in the conjunctiva. Estimates suggest that less than 5 percent of a topical ophthalmic drug reaches target tissues (3). The challenge when it comes to treating disease, whether at the front or the back of the eye, is achieving effective drug concentrations for prolonged periods of time while minimizing side effects (and overcoming adherence challenges).
Developments in the treatment of retinal disease have ushered in implantable pharmacotherapies that allow controlled release of the drug to specific targets in the eye. And we continue to see interesting research and development into sustained-release intraocular alternatives to traditional topical and systemic ocular therapies. Sustained-release delivery platforms have grown in popularity throughout medicine and are well suited in ophthalmology – particularly for chronic diseases. Whether the regimen includes topical drops or injections, the need for consistent dosing day after day, month after month, can take a significant toll. Sustained-release medications can help ease the burden on both patients and physicians.
Platforms and products
An early entrant into the sustained-release ophthalmic drug category is Lacrisert (hydroxypropyl cellulose insert, Bausch + Lomb), a once-daily self-administered lubricating insert for patients with dry eye disease (DED). Though it does not directly address the inflammatory aspect of DED, Lacrisert can be especially helpful to patients who are using artificial tears multiple times a day. It is indicated for moderate-to-severe DED and, because it is preservative free, it can work well in contact lens wearers (4). Once inserted, the implant softens and slowly dissolves to help stabilize the tear film. Lacrisert can be administered before bed at night, which is beneficial for patients who experience blurred vision or foreign body sensation.
Historically, the posterior segment has seen relatively more development in sustained-release implants. Retisert (fluocinolone acetonide 0.59 mg, Bausch + Lomb), a three-year intraocular implant indicated for chronic noninfectious posterior uveitis, was approved by the FDA in 2005. It is administered surgically and, though it is effective in minimizing inflammatory flare ups, it is associated with intraocular pressure (IOP) elevation, glaucoma surgery, and cataract development (5).
Iluvien (fluocinolone acetonide 0.19 mg, Alimera Sciences) and Yutiq (fluocinolone acetonide 0.18 mg, EyePoint Pharmaceuticals) provide a lower dose of steroid to the posterior segment, also for three years. These implants offer efficacy in treating diabetic macular edema (DME) and chronic posterior uveitis, respectively, but with substantially reduced incidence of IOP and cataract complications (6, 7). A shorter-duration, bioerodible intravitreal implant, Ozurdex (dexamethasone 0.7 mg, Allergan) is used to treat macular edema secondary to branch or central retinal vein occlusion (RVO), DME, and posterior uveitis (8). Iluvien, Yutiq, and Ozurdex, notably, are administered via in-office intravitreal injection.
Sustained-release approaches to the delivery of anti-VEGF agents are also of great interest; the closest to approval is perhaps the ranibizumab port delivery system (PDS; Genentech). Challenges in formulating anti-VEGF molecules for sustained delivery in a way that preserves their structure can be overcome by the PDS, which is a refillable reservoir implanted via a surgical procedure, or by nanoformulations, hydrogels, and other encapsulation techniques in development (9).
Post-op pain and inflammation
More recently, the anterior segment has seen the welcome introduction of sustained-release corticosteroid options to minimize the need for patient administration of postoperative drops. Dexycu (dexamethasone intraocular suspension 9%, EyePoint Pharmaceuticals) is the first FDA-approved intraocular corticosteroid administered as a single injection to treat postoperative inflammation. Its approval was followed by Dextenza (dexamethasone ophthalmic insert 0.4 mg, Ocular Therapeutix), an intracanalicular insert indicated for the treatment of ocular inflammation and pain after ophthalmic surgery.
Dexycu is formulated using proprietary Verisome sustained-release technology – a cohesive, bioerodible liquid steroid depot that is injected into the ciliary sulcus at the end of ocular surgery, where it delivers a tapering dose of dexamethasone for about 21 days. In controlled clinical studies, Dexycu provided a significant anti-inflammatory effect (comparable to QID topical prednisolone drops) that began early and was sustained throughout the postoperative period (10, 11). The Verisome technology enables Dexycu to immediately deliver and maintain a therapeutic concentration of the steroid at the target site. The steroid is released at its highest concentration in the first two weeks, with a naturally decreasing concentration over – and after – that period. Such tapering is similar to how we traditionally use our topical steroids, but it eliminates the need for patients to understand or remember the schedule. Although the pivotal trials for Dexycu were conducted in cataract surgery, it is approved for any ocular surgery and has been used for post-op inflammation control in MIGS procedures and even vitreoretinal surgeries (12).
Dextenza is inserted into the lower lid canaliculus at the end of ocular surgery and is currently being investigated for the treatment of allergic conjunctivitis (13). Dextenza uses a resorbable hydrogel vehicle to deliver a tapering dose of medication to the ocular surface for 30 days, as it gradually resorbs (14). The product is preservative-free and conjugated with a small amount of fluorescein that enables visualization. It also provides occlusion of the punctum, which may be helpful for patients with DED. If there is a pressure spike, the implant can be irrigated or expressed out. Ophthalmic surgeons and consultants at my practice participated in clinical trials for Dextenza and have used both Dextenza and Dexycu in practice, and found them to be safe and effective with minimal postoperative pressure spikes or breakthrough inflammation. These new drug delivery platforms are a major step forward, extending our armamentarium so that we can better tailor therapy to meet individual patients’ needs.
Glaucoma paradigm shift
The most recent entrant into the sustained-release ophthalmic drug arena to receive FDA approval is Durysta (bimatoprost 10 µg implant, Allergan). This is the first intracameral, biodegradable sustained-release implant indicated to reduce IOP in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). FDA approval was based on results from two phase 3 studies of 1,122 patients with OAG or OHT that evaluated the safety and efficacy of Durysta compared to twice-daily topical timolol drops (15). Bimatoprost SR reduced IOP by 30 percent during a 12-week period, demonstrating noninferiority to timolol with a single administration. In real-world practice, it is expected that Durysta will be administered quarterly, making it a true paradigm shift in the medical treatment of glaucoma.
Extraocular rings, drug-secreting contact lenses, nanoparticles, modified molecules, hydrogels, photo cross-linked biodegradable technologies, and stem cells are among the innovative vehicles that we will undoubtedly see move from the developmental pipeline into the clinic and OR. Now that cataract, retina and even glaucoma patients are benefiting from sustained-release drug technology, my hope for the not-too-distant future is for dry eye and allergy patients to access the same levels of convenience, cost savings, and precision.
Relevant disclosures: Allergan, OTX, EyePoint, and Bausch + Lomb.
- J An et al., “Evaluation of eyedrop administration by inexperienced patients after cataract surgery,” J Cataract Refract Surg, 40, 1857 (2014). PMID: 25248295.
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- J Luchs et al., “Efficacy of hydroxypropyl cellulose ophthalmic inserts (LACRISERT) in subsets of patients with dry eye syndrome: findings from a patient registry,” Cornea, 29, 1417 (2010). PMID: 20847657.
- G Jaffe et al., “Fluocinolone Acetonide Uveitis Study Group. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four–week results of a multicenter randomized clinical study,” Ophthalmology, 1, 113, 1020 (2006). PMID: 16690128.
- P Campochiaro et al., “FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema,” Ophthalmology, 119, 2125 (2012). PMID: 22727177.
- G Jaffe et al., “Effect of a fluocinolone acetonide insert on recurrence rates in noninfectious intermediate, posterior, or panuveitis: 3-year results,” Ophthalmology (2020). PMID: 30367884.
- Allergan, “Ozurdex [package insert],” May (2018).
- I Seah et al., “Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases,” Eye, 30, 1 (2020). PMID: 32444861.
- E Donnenfeld et al., “Dexamethasone intracameral drug-delivery suspension for inflammation associated with cataract surgery: a randomized, placebo-controlled, phase III trial,” Ophthalmology, 125, 799 (2018). PMID: 29397189.
- E Donnenfeld et al., “Safety of IBI-10090 for inflammation associated with cataract surgery: Phase 3 multicenter study,” J Catract Refract Surg, 44, 1236 (2018). PMID: 30139638.
- D Kiernan, “Dexamethasone intracameral drug-delivery suspension for inflammation associated with vitreoretinal surgery,” MJ Open Ophthalmology, 5 (2020). PMID: 32426525.
- K Kenyon et al., “Phase 3 trial evaluating an intracanalicular dexamethasone insert (0.4 mg) for the treatment of patients with allergic conjunctivitis,” Presented at the American Society of Cataract and Refractive Surgery Annual Meeting; May 16-17, 2020.
- S Tyson et al., “Multicenter randomized phase 3 study of a sustained-release intracanalicular dexamethasone insert for treatment of ocular inflammation and pain after cataract surgery,” J Cataract Refract Surg, 45, 204 (2019). PMID: 30367938.
- Allergan. Available at: prn.to/2YGcRfU.