The future is bright for the treatment of intraocular inflammation. Therapeutic options for uveitis have grown tremendously over the last decade. The US Food and Drug Administration (FDA) has approved a number of extended-duration intraocular steroids that last for months to years in the treatment of noninfectious uveitis (NIU) of the posterior segment, including the dexamethasone implant 0.7 mg (Ozurdex; Allergan), the surgical fluocinolone acetonide implant 0.59 mg (Retisert; Bausch + Lomb), and the in-office fluocinolone acetonide insert 0.18 mg (Yutiq; Eyepoint Pharmaceuticals). Simultaneously, the number of systemic immunosuppressive therapeutic options has increased with the addition of medications that target novel inflammatory pathways and have shown efficacy in treating both systemic and ocular disease.

LOCAL STEROID THERAPY

Corticosteroids remain a tried-and-true therapeutic option for the treatment of NIU. However, the use of systemic corticosteroids at doses greater than 5 mg per day for longer than 3 months places patients at high risk of systemic adverse effects (AE). Local steroids can avoid these systemic AE with sustained-release options providing extended duration; however, to rule out infectious causes of uveitis, we avoid local therapy as a first-line option until we are sure a patient responds well to systemic steroid therapy.

Fluocinolone Acetonide Insert 0.18 mg

Yutiq, the nonbioerodible 0.18 mg fluocinolone acetonide insert (FAi), was approved by the FDA in October 2018 for the treatment of posterior NIU. It is an in-office intravitreal implant placed with a 25-gauge injector and has been approved for the treatment of posterior NIU for up to 3 years.¹ The 36-month, phase 3 clinical trial compared the FAi to sham injection and revealed significantly lower uveitis recurrence rates in the insert group at 6 months (28% vs 91%, P<.001), 12 months (38% vs 98%, P<.001), and 36 months (66% vs 98%, P<.001).¹

Similar percentages of patients from both groups were started on medications to lower intraocular pressure (IOP) (42.5% for FAi and 33.3% for sham).¹ Of patients from the FAi group, 5.7% required IOP-lowering surgery, whereas 11.9% of the sham group required IOP-lowering surgery, presumably due to the need for rescue therapy in the sham group.¹ As expected from an intraocular steroid, more patients from the FAi group required cataract surgery (73.8%) by 36 months than did those in the sham group (23.8%).

Suprachoroidal Triamcinolone Acetonide

Suprachoroidal delivery of triamcinolone acetonide (Xipere; Clearside Biomedical) is a novel method for local corticosteroid administration that is currently being evaluated in clinical trials for the treatment of macular edema associated with diabetes, retinal vein occlusion, and posterior NIU.^2-6 The phase 1 and 2 clinical trials of suprachoroidal delivery of triamcinolone acetonide (CLS-TA) revealed encouraging outcomes in the treatment of posterior NIU with good preliminary safety and efficacy data.^4,5 Results of the recently published phase 3 clinical trial (PEACHTREE) revealed that CLS-TA every 12 weeks resulted in 47% of patients achieving an improvement of ≥15 ETDRS letters by week 24, compared to just 16% of those who received a sham injection (P<.001).⁶ There was a statistically significant decrease in optical coherence tomography (OCT) central subfield thickness (CST) in those receiving CLS-TA (153 μm) compared to sham (18 μm, P<.001).⁶

The most common adverse event (AE) was ocular pain at the time of the procedure.⁶ Intraocular pressure elevation occurred in 11.5% of the treatment arm and 15.6% of the control arm.⁶ Notably, all patients who had an IOP elevation in the control arm had received rescue therapy with local corticosteroids.⁶ The formation of cataract was comparable between the CLS-TA and sham groups at 7.3% and 6.3%, respectively.⁶ The lower incidence of cataract and IOP elevation with CLS-TA compared to other local steroid options makes it a favorable future alternative therapy; however, longer term studies with repeat injections will be needed to determine what the true incidence of cataract and IOP elevation are with repeated treatment.

Transscleral Iontophoresis of Dexamethasone Phosphate

Iontophoresis employs an electrical gradient to push a polarized drug into the eye. Iontophoretically delivered medications have been used to treat various localized pathologies, including pain, inflammation, infections, and dermatologic cancers.⁷ Recently, this method has been utilized to transsclerally deliver a polarized steroid, dexamethasone phosphate, in the treatment of anterior NIU (EGP-437 and EyeGate II; EyeGate Pharmaceuticals). While the results of the initial phase 1, dose-finding trial were encouraging,⁸ the phase 2/3 trial of dexamethasone phosphate delivered by iontophoresis failed to meet statistical noninferiority compared to a traditional topical prednisolone acetate taper in the treatment of anterior NIU.⁹ Iontophoresis was performed on days 0 and 7. At day 14, 33.3% of the study arm and 33.0% of the control arm achieved the primary endpoint of an anterior chamber cell count of zero, resulting in a noninferiority margin of -12.94%, just exceeding the preset threshold of -10%.⁹ Despite not meeting their primary endpoint of noninferiority, the authors discussed the benefits of transscleral iontophoresis including simplified treatment regimen, fewer IOP elevations, and possibly better efficacy for more severe disease.⁹

LOCAL NONSTEROIDAL THERAPY

Although local steroids avoid the systemic AE associated with systemic steroids or immunosuppressive therapy, they still carry increased risk of cataract and steroid-response glaucoma. An ideal agent to treat NIU would be a local, nonsteroidal, immunosuppressive drug avoiding the local AE of steroids and the systemic AE of immunosuppressants.

Sirolimus

Sirolimus (Opsiria; Santen) is a macrolide triene antibiotic that also possesses immunosuppressive properties through inhibition of mammalian target of rapamycin (mTOR), which has been recently repurposed for the treatment of posterior NIU.¹⁰ The first of 2 phase 3 clinical trials (SAKURA 1) evaluated efficacy of sirolimus in the treatment of posterior NIU.¹¹ In SAKURA 1, intravitreal sirolimus of escalating doses (44 μg, 440 μg, and 880 μg) were randomly assigned to participants in a 1:1:1 fashion.¹¹ The assigned sirolimus dose was given every 60 days for 3 doses.¹¹ A significantly higher proportion of the 440 μg arm reaching the primary endpoint of vitreous haze (VH) score of 0 at 6 months (22.8%) compared to the 44 μg active control arm (10.3% respectively, P=.025).¹¹ Unexpectedly, the 880 μg group was not superior to the 44 μg group(16.4%, P=.182).¹¹ Patients who met the primary outcome goal were also more likely to be tapered off of steroids if they were on the 440 μg dose compared to the 44 μg dose (26.9% vs 0.0%, P=.0113).¹¹

The results of the SAKURA 1 and 2 study have recently been published in combination.¹² The combined analysis of the 2 phase 3, randomized, double-masked clinical trials revealed significantly higher proportions of patients in the 440 μg arm achieved a VH of 0 (21.2%) at month 5 compared to the 44 μg active control arm (13.5%, P=.038).¹² SAKURA 2 enrollment in the 880 μg arm was terminated early after the results of SAKURA 1 were released.¹² The combined report did release the isolated SAKURA 2 primary outcome data.¹² The percentage of patients that reached the primary endpoint of a VH score of 0 was 17.6%, 19.1%, and 13.3% in the 44 μg, 440 μg, and 880 μg groups, respectively.¹² Neither of the treatment arms (440 μg or 880 μg) were statistically different from the active control arm in reaching the primary outcome (P=.783 and P=.485, respectively).¹²

Adverse events of cataract (1.0%, 0.5%, and 2.2%) and IOP elevation (1.0%, 1.5%, and 0.6%) were comparable across each dose arm (44 μg, 440 μg, and 880 μg, respectively) in the combined SAKURA data.¹² The promise of a local, nonsteroidal therapy with lower incidence of cataract and IOP rise is appealing. However, in December 2017 the FDA did not approve the use of intravitreal sirolimus with the current phase 3 clinical trial data and requested substantiating evidence to demonstrate its efficacy in treating posterior NIU. Another phase 3 trial is currently enrolling patients.

SYSTEMIC NONSTEROIDAL THERAPY

Systemic immunosuppressive drugs remain a cornerstone of therapy in the treatment of NIU. There are currently a few promising systemic medications in clinical trials specifically for the treatment of NIU.

Filgotinib

Filgotinib (Gilead Sciences) is an oral JAK1-inhibitor that is presently in multiple clinical trials for the treatment of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, ankylosing spondylitis, and uveitis. The phase 2, placebo-controlled, double-masked clinical trial comparing filgotinib 200 mg orally once daily to placebo in the treatment of active noninfectious intermediate, posterior, or panuveitis is currently under investigation.¹³ The primary outcome measure is time to treatment failure as all patients are tapered off a protocol-defined oral steroid regimen.¹³

Sarilumab

Sarilumab (Kevzara; Sanofi Genzyme) is a subcutaneously injected monoclonal antibody targeted against the interleukin-6 receptor complex.¹⁴ It is currently FDA approved for the treatment of rheumatoid arthritis.¹⁵ In the phase 2 clinical trial (SATURN) comparing sarilumab 200 mg dosed every 2 weeks to placebo, the treatment arm failed to meet its primary endpoint of a ≥2-step reduction in VH (by a central reading center) or systemic corticosteroid dose of <10 mg/day by week 16 (46.1% vs 30.0%, P=.2354).¹⁴ However, the sarilumab group did have a significant reduction in VH by investigator assessment (64.0% vs 35.0%, P=.0372) and a greater visual acuity gain (8.9 letters vs 3.6 letters, P=.0333).¹⁴ The most common ocular AE were worsening uveitis and retinal infiltrates.¹⁴ The most common nonocular AE were cough and headache.¹⁴

Tocilizumab

Tocilizumab (Actemra; Genentech) is a monoclonal antibody targeted against the interleukin-6 receptor. The results of the phase 1/2, randomized, open-label clinical trial (STOP-UVEITIS) comparing every-4-week infusions of tocilizumab 4 mg/kg (group 1) to 8 mg/kg (group 2) in patients with noninfectious intermediate, posterior, or panuveitis.¹⁶ At 6 months, 43.5% of patients reached the primary endpoint of a 2-step reduction in VH (40.0% of group 1 and 46.1% of group 2; P<.05).¹⁶ Similarly, there was a significant overall visual acuity gain (+8.22 letters, P<.01).¹⁶ There was no statistical difference between the 2 treatment groups (+10.9 letters vs +5.5 letters, P>.05).¹⁶ Central macular thickness significantly decreased in both groups, with a statistically greater reduction in the 4 mg/kg group (-131.5 vs -38.91 μm, P<.05).¹⁶

Infusions of tocilizumab were reportedly well tolerated in both studies.^16,17 The most common reported AE were injection-site reaction, arthralgias, sinus congestion, and rhinorrhea.^16,17

EMERGING NOVEL THERAPIES

EYS606

Electrotransfection uses an electrical gradient to move DNA, RNA, and protein into cells without the traditional use of a viral vector. EYS606 (EyeCET; Eyevensys) is an electrotransfection injection system that delivers nonviral plasmids encoding for the production of a novel anti-TNFα antibody into the ciliary body. This treatment is positioned to be a sustained local therapy that avoids the local AE of steroids and the systemic AE of immunomodulatory therapy. The EYS606 phase 2 clinical trial (ELECTRO) is ongoing, assessing its safety and efficacy in the treatment of noninfectious intermediate, posterior, and panuveitis.

Autologous Treg Infusions

The use of autologous Treg cell infusions has been evaluated in the reduction of transplant rejection and has been investigated in some autoimmune disorders, such as type 1 diabetes and Crohn disease.^18,19 Treg cells play an important role in the inflammatory and immune cascades by inhibiting the antibody production, antigen-presenting cell function, and helper and cytotoxic T-cell responses.^18,19 A phase 1 clinical trial (UVEREG) has been registered to evaluate the safety of intravitreal Treg injections for the treatment of bilateral NIU.²⁰

CONCLUSION

The future is exciting for uveitis treatment, with new delivery modalities for our tried-and-true corticosteroids and active clinical trials for local, nonsteroidal intravitreal and systemic medications specifically for the treatment of NIU. Even more exciting are the clinical trials assessing completely novel methods of treating uveitis. As our armamentarium grows, so will our ability to treat this complex ocular disease.

References

1. Jaffe GJ, Pavesio CE; Study Investigators. Effect of a fluocinolone acetonide insert on recurrence rates in noninfectious intermediate, posterior, or panuveitis: three-year results. Ophthalmology. 2020;127(10):1395-1404.
2. Wykoff CC, Khurana RN, Lampen SIR, et al; HULK Study Group. Suprachoroidal triamcinolone acetonide for diabetic macular edema: the HULK trial. Ophthalmol Retina. 2018;2(8):874-877.
3. Campochiaro PA, Wykoff CC, Brown DM, et al; Tanzanite Study Group. Suprachoroidal triamcinolone acetonide for retinal vein occlusion: results of the Tanzanite study. Ophthalmol Retina. 2018;2(4):320-328.
4. Goldstein DA, Do D, Noronha G, Kissner JM, Srivastava SK, Nguyen QD. Suprachoroidal corticosteroid administration: a novel route for local treatment of noninfectious uveitis. Transl Vis Sci Technol. 2016;5(6):14.
5. Yeh S, Kurup SK, Wang RC, et al; DOGWOOD Study Team. Suprachoroidal injection of triamcinolone acetonide, CLS-TA, for macular edema due to noninfectious uveitis: a randomized, phase 2 study (DOGWOOD). Retina Phila Pa. 2019;39(10):1880-1888.
6. Yeh S, Khurana RN, Shah M, et al; PEACHTREE Study Investigators. Efficacy and safety of suprachoroidal CLS-TA for macular edema secondary to noninfectious uveitis: phase 3 randomized trial. Ophthalmology. 2020;127(7):948-955.
7. Karpiński TM. Selected medicines used in iontophoresis. Pharmaceutics. 2018;10(4):204.
8. O’Neil EC, Huang J, Suhler EB, et al. Iontophoretic delivery of dexamethasone phosphate for non-infectious, non-necrotising anterior scleritis, dose-finding clinical trial. Br J Ophthalmol. 2018;102(8):1011-1013.
9. Sheppard J, Garg S, Lievens C, et al. Iontophoretic dexamethasone phosphate compared to topical prednisolone acetate 1% for noninfectious anterior segment uveitis. Am J Ophthalmol. 2020;211:76-86.
10. Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003;35(3 Suppl):7S-14S.
11. Nguyen QD, Merrill PT, Clark WL, et al; Sirolimus study Assessing double-masKed Uveitis tReAtment (SAKURA) Study Group. Intravitreal sirolimus for noninfectious uveitis: a phase III sirolimus study assessing double-masked uveitis treatment (SAKURA). Ophthalmology. 2016;123(11):2413-2423.
12. Merrill PT, Clark WL, Banker AS, et al. Efficacy and safety of intravitreal sirolimus for noninfectious uveitis of the posterior segment: results from the sirolimus study assessing double-masked uveitis treatment (SAKURA) program. Ophthalmology. 2020;127(10)1405-1415.
13. A phase 2, randomized, placebo-controlled trial evaluating the efficacy and safety of filgotinib in subjects with active noninfectious uveitis. Clinicaltrials.gov Identifier: NCT03207815. https://clinicaltrials.gov/ct2/show/NCT03207815 . Updated October 19, 2020. Accessed October 21, 2020.
14. Heissigerová J, Callanan D, de Smet MD, et al. Efficacy and safety of sarilumab for the treatment of posterior segment noninfectious uveitis (SARIL-NIU): the phase 2 SATURN study. Ophthalmology. 2019;126(3):428-437.
15. US Food and Drug Administration. Kevzara (sarilumab) injection. Accessed August 15, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761037Orig1s000TOC.cfm
16. Sepah YJ, Sadiq MA, Chu DS, et al. Primary (month-6) outcomes of the STOP-Uveitis study: evaluating the safety, tolerability, and efficacy of tocilizumab in patients with noninfectious uveitis. Am J Ophthalmol. 2017;183:71-80.
17. Ramanan AV, Dick AD, Guly C, et al. Tocilizumab in patients with anti-TNF refractory juvenile idiopathic arthritis-associated uveitis (APTITUDE): a multicentre, single-arm, phase 2 trial. Lancet Rheumatol. 2020;2(3):e135-e141.
18. Desreumaux P, Foussat A, Allez M, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology. 2012;143(5):1207-1217.e2.
19. Bluestone JA, Buckner JH, Fitch M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7(315):315ra189.
20. Treatment of the Bilateral Severe Uveitis by IVT of Regulator T-Cells: Study of Tolerance of Dose. Clinicaltrials.gov Identifier: NCT02494492. https://clinicaltrials.gov/ct2/show/NCT02494492 . Updated August 16, 2017. Accessed October 21, 2020.