New and different therapies emerging through uveitis pipeline


Local therapy plays a significant role in the treatment of uveitis, either as monotherapy or in combination therapy. Alongside a number of pharmacotherapeutic agents, new products and technologies are in development that could expand clinicians’ options and improve outcomes.

Take-home: New drugs and new delivery methods, many in clinical trials, may offer clinicians additional therapeutic options for the treatment of uveitis.

Local therapy plays a significant role in the treatment of uveitis, either as monotherapy or in combination therapy. Alongside a number of pharmacotherapeutic agents, new products and technologies are in development that could expand clinicians’ options and improve outcomes.

“Properly delivered, both by route and dose, local therapy can provide steady control of inflammation to achieve zero tolerance of inflammatory activities,” said Quan Dong Nguyen, MD, FAAO, professor of ophthalmology, Stanford University, Stanford, CA.

Local nonsteroidal, anti-inflammatory agents are among the most common local therapies, and one of the products in the pipeline is the investigational aldehyde trap (ADX-2, formerly known as NS2, Aldeyra Therapeutics). ADX-2 is an amine that binds and traps pro-inflammatory and cytotoxic aldehydes. A topical formulation is undergoing clinical trials for the treatment of anterior uveitis as well as allergic conjunctivitis.

Results of a phase II clinical trial in May 2016 demonstrated activity comparable to corticosteroids in reducing anterior chamber cell count in patients with noninfectious anterior uveitis, said Dr. Nguyen. A phase III trial is planned.

While therapies such as ADX-2 are promising, local corticosteroids remain the first-line treatment for noninfectious anterior uveitis. Steroids can be administered by intravitreal or intraocular routes, and there are two approved delivery systems, a dexamethasone implant (Ozurdex, Allergan) and a fluocinolone implant (Retisert, Bausch + Lomb).

A second phase III trial of a fluocinolone insert (Medidur, pSivida) has met its target enrollment and is now underway, and results are expected soon, Dr. Nguyen said. A previous phase III study of this sustained-release technology met the primary endpoint of prevention of recurrence of posterior segment uveitis at 6 months.

Novel injection technique

Regional or suprachoroidal administration of triamcinolone is also being evaluated, according to Dr. Nguyen, who was one of the investigators in the Dogwood clinical trial of one device. In this randomized, masked, controlled, multicenter phase II study in patients with macular edema secondary to uveitis, individuals were treated with a novel suprachoroidal-injection technique developed by Clearside Biomedical using a proprietary formulation of triamcinolone.                             

Results reported in August 2016 showed a significant reduction in macular edema at 2 months in patients who had received a 4 mg dose of triamcinolone (n = 16, p = 0.0017), Dr. Nguyen said. Vitreous haze also improved. No corticosteroid-related increases in intraocular pressure (IOP) were reported in either the phase I or phase II study.

“Suprachoroidal delivery of corticosteroid may be a potential approach to consider in the future,” Dr. Nguyen said, adding that enrollment in a phase III trial of this technology is ongoing.

Local steroidal agents used to treat noninfectious uveitis include the familiar topical drugs prednisolone and difluprednate. Iontophoresis–the delivery of dexamethasone through a low-level electrical current–is an alternative approach.  

Iontophoresis technology

With transscleral iontophoresis technology (EGP-437) developed by EyeGate Pharma, charged particles are delivered to the cornea to target the inflammation, Dr. Nguyen said. It may be possible to deliver higher ocular drug concentrations with this system than with traditional topical application, resulting in a sustained therapeutic effect and reduced dosing frequency.

In an initial phase III, non-inferiority anterior uveitis trial, 193 subjects were randomized to 2 EGP-437 iontophoresis treatments with placebo eye drops or 2 placebo iontophoresis treatments with prednisolone acetate eye drops. A similar response rate was achieved when EGP-437 treatment was compared to the standard of care treatment with prednisolone.

Further, fewer subjects in the EGP group had an IOP increase than in the prednisolone group (15%, n = 14 versus 25%, n = 24) Dr. Nguyen said. There were 2.4 times the number of incidents of IOP increase in the control, state-of-care arm, 41 versus 17.

A confirmatory phase III trial is underway. The primary endpoint is the proportion of subjects with anterior chamber cell count of zero at day 14.

Immunomodulatory therapy

New approaches are being explored in local immunomodulatory therapy, Dr. Nguyen said. Complement-based therapy in patients with active noninfectious intermediate, posterior, or panuveitis, is being investigated in an ongoing phase II clinical trial of intravitreal delivery of the complement inhibitor LFG316 (Novartis), a monoclonal antibody directed toward human C5.

Trials are in progress for intravitreal delivery of sirolimus (Santen), a novel immunoregulatory agent. This mTOR inhibitor is being assessed for management of patients with noninfectious uveitis of the posterior segment. In a 6-month, phase III study, patients were randomized to receive 44 µg, 440 µg, or 880 µg doses of intravitreal sirolimus at days 1, 60, and 120. The primary efficacy outcome was the percentage of subjects with vitreous haze equaling zero at month 5.

“For the primary endpoint, patients in the 440-µg group demonstrated statistically significant improvement (p = 0.25) over the 44-µg and 880-µg groups,” Dr. Nguyen said.

Results for a key secondary endpoint, the proportion of subjects with vitreous hemorrhage equaling zero or 0.5+ at month 5, were even more significant (p = 0.008). In the 440-µg group, 52.6% of subjects met this target compared to 43.1% in the 880-µg group and 35% in the 44-µg group.

The highest median gain in best-corrected visual acuity from baseline was 10.5 letters among patients in the 440-µg arm who had a baseline measurement <20/100 and displayed the most potential to improve, Dr. Nguyen added.

Based on study findings, it appears that intravitreal sirolimus 440 µg controls inflammation in target tissues in the posterior segment by inhibiting mTOR and can reduce inflammation while preserving vision.

“The benefit:risk profile seems to favor its potential use for the long-term treatment of noninfectious posterior segment uveitis,” Dr. Nguyen said.

Dr. Nguyen and colleagues in the Sirolimus study Assessing double-masKed Uveitis tReatment Study Group (SAKURA) published their findings in Ophthalmology in November 2016.


Quan Dong Nguyen, MD

P: 650-723-6995


This article was based on a presentation given by Dr. Nguyen during Uveitis Subspecialty Day at the 2016 American Academy of Ophthalmology meeting. Dr. Nguyen is a consultant/advisor to Santen Inc., Bausch + Lomb, Genentech, Regeneron Pharmaceuticals, Allergan, Bayer Healthcare Pharmaceuticals, and Oligasis. He has received grant support from Genentech, Regeneron Pharmaceuticals, pSivida, AbbVie, and XOMA.

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