Innovations in sustained-delivery options: Focus on chronic inflammation
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This two-part series will review innovative sustained-delivery options in the retina space for both long- and short-term indications.
In part 1, I discuss implants designed to treat chronic inflammation. Part 2 will cover postoperative sustained-release steroids.
Source: Adobe Stock
Diseases of the choroid and retina are diverse in their underlying pathology, patient profiles and treatments. In many cases, underlying disease processes necessitate long-term, repeated treatment. Fortunately, we have seen recent innovations designed to meet this challenge, with sustained-release corticosteroids available for conditions such as chronic noninfectious uveitis (CNIU), diabetic macular edema and others (Table 1).
Chronic noninfectious uveitis
In CNIU, treatment must provide long-term inflammation control, as recurrence of inflammation can lead to cumulative damage and vision loss. Traditional localized corticosteroids tend to be limited in treatment duration, and while systemic corticosteroids and other immunosuppressants offer long-term efficacy, they come with possible systemic side effects and the burden of daily treatment.
Retisert (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb) offered an alternative, providing a steady dose for about 30 months after surgical implantation. In clinical trials, patients treated with Retisert had lower rates of recurrence at 34 weeks after implantation than during the 34 weeks before implantation.
The MUST trial compared Retisert with systemic therapy in patients with noninfectious intermediate, posterior or panuveitis. Both treatment groups improved in visual acuity to about the same degree at 24 months. Retisert-treated eyes, however, exhibited less uveitis activity than eyes of patients treated with systemic therapy. On the other hand, the MUST trial also highlighted Retisert’s greater liability for IOP elevation. Incidence of IOP of 30 mm Hg or higher at 24 months was 33% for Retisert and 6% for systemic treatment.
In 2018, Yutiq (fluocinolone acetonide intravitreal implant 0.18 mg, EyePoint Pharmaceuticals) was introduced as an alternative sustained-release option for treating CNIU. Yutiq, administered in the office setting, delivers drug at a much lower rate than Retisert. I use Yutiq in all appropriate eyes and have not had to supplement any of them with additional corticosteroids or other uveitis therapies.
In two sham-controlled trials of Yutiq, the 6-, 12- and 36-month follow-up data consistently show that Yutiq-treated eyes had significantly fewer uveitis recurrences than sham-treated treated eyes. Up to month 36, incidence of IOP higher than 30 mm Hg was 16.1% for Yutiq and 11.9% for sham.
Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan) is a shorter-lived bioerodible alternative to Retisert and Yutiq, lasting up to 6 months. In a study in intermediate or posterior CNIU, 47% of eyes treated with Ozurdex achieved vitreous haze score of 0 at 8 weeks vs. 12% of sham-treated eyes. The rate of IOP of 25 mm Hg or higher was 7.1% for Ozurdex and 4.2% for sham.
Macular edema
In DME and macular edema associated with branch or central retinal vein occlusion, intravitreal injection of a VEGF inhibitor has become first-line treatment. However, not all patients respond satisfactorily; some, such as those with recent cardiovascular events, may be inappropriate for anti-VEGF treatment, and the need for frequent injections — monthly, at least during the first 5 to 6 months — can be challenging for patients and lead to interruptions in care. Therefore, a role remains for sustained-release corticosteroids in these conditions.
Iluvien (fluocinolone acetonide intravitreal implant 0.19 mg, Alimera Sciences) was evaluated in two 3-year sham-controlled trials in DME. At both 2 and 3 years, more Iluvien-treated than sham-treated patients showed improvement in best corrected visual acuity. Adverse events related to IOP were reported in 37% of Iluvien-treated patients vs. 12% assigned to sham.
Two-year data from a real-world study of Iluvien in patients with DME demonstrated stable mean IOP between pre- and post-implantation periods but an increase in the number of patients requiring IOP-lowering medications (40% vs 9.6%).
Ozurdex was also evaluated in DME in two 3-year sham-controlled trials in which it demonstrated efficacy in improving BCVA. One Ozurdex treatment also improved BCVA at 6 months in patients with BRVO- or CRVO-related macular edema. Based on current recommendation, re-treatment with Ozurdex in these patients is generally performed after 3 to 4 months, averaging two to three injections per year.
Safety concerns with Ozurdex include IOP elevation and cataract. In a large observational study, ocular hypertension (IOP 25 mm Hg or higher or 10 mm Hg or higher increase) occurred in 28% of eyes.
Looking ahead
Sustained delivery of anti-VEGF agents is a promising development. Also being explored are gene therapy approaches to anti-VEGF treatment, which hold the potential of long-term continuous expression of anti-VEGF protein.
In the treatment of vitreoretinal diseases, we face numerous practical and physiological barriers to controlling disease activity. Innovations in sustained-release ophthalmic drugs provide us with increasingly sophisticated tools for long-term disease management and preservation of vision.
- References:
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- Jaffe GJ. Treatment of non-infectious uveitis that affects the posterior segment with a single intravitreal fluocinolone acetonide insert (FAi) – 3-year results. Presented at: Association for Research in Vision and Ophthalmology meeting; April 28-May 2, 2019; Vancouver.
- Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, et al. Ophthalmology. 2011;doi:10.1016/j.ophtha.2011.07.027.
- Lowder C, et al. Arch Ophthalmol. 2011;doi:10.1001/archophthalmol.2010.339.
- Mansour SE, et al. Br J Ophthalmol. 2021;doi:10.1136/bjophthalmol-2020-315984.
- Malclès A, et al. Retina. 2017;doi:10.1097/IAE.0000000000001369.
- Multicenter Uveitis Steroid Treatment (MUST) Trial Follow-Up Study Research Group. Ophthalmology. 2015;doi:10.1016/j.ophtha.2015.06.043.
- Nguyen QD, et al. Minimizing recurrences of ocular inflammation and need for adjunctive treatment of non-infectious posterior uveitis (NIPU) during the 2 years following treatment with a single 0.18 mg fluocinolone acetonide intravitreal insert (FAi). Presented at: Association for Research in Vision and Ophthalmology meeting; April 28 -May 2, 2019; Vancouver.
- Schmidt-Erfurth U, et al. Ophthalmologica. 2019;doi:10.1159/000502041.
- Singer MA. Fluocinolone acetonide intravitreal insert for non-infectious posterior uveitis: analysis of significant IOP elevation. Presented at: American Academy of Ophthalmology meeting; Oct. 12-15, 2019; San Francisco.
- For more information:
- Daniel F. Kiernan, MD, FAAO, FACS, can be reached at The Eye Associates, 2111 Bee Ridge Road, Sarasota, FL 34239; email: danielkiernan714@yahoo.com.
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