Randomized Phase 2 Trial of Reproxalap, a Novel Reactive Aldehyde Species Inhibitor, in Patients with Noninfectious Anterior Uveitis: Model for Corticosteroid Replacement

Abstract

Purpose: Topical corticosteroids used to treat ocular inflammation are associated with a high risk of clinically significant toxicities. Therefore, corticosteroid-sparing medications to treat ocular inflammation are needed. Noninfectious anterior uveitis (NAU) is a sight-threatening ocular inflammatory condition typically treated with topical corticosteroids. This corticosteroid-controlled comparator trial examines the safety and efficacy of reproxalap, a novel inhibitor of reactive aldehyde species (RASP), for the treatment of ocular inflammation, by using NAU as a model. Methods: Forty-five patients with mild-to-moderate acute NAU were randomly assigned 1:1:1 to receive reproxalap 0.5% ophthalmic solution (4 times daily for 6 weeks), prednisolone 1% ophthalmic solution (Pred Forte®, 4 times daily taper for 6 weeks), or a combination of reproxalap 0.5% ophthalmic solution (4 times daily for 6 weeks) and prednisolone 1% ophthalmic solution (twice daily taper for 6 weeks). Results: All treatments improved anterior cell count and grade, and no differences were observed in change from baseline between groups. Reproxalap monotherapy and combination therapy were statistically noninferior to prednisolone. The proportion of patients requiring rescue therapy was comparable across treatment groups. No safety issues were identified for reproxalap-treated patients, whereas treatment with prednisolone resulted in an average increase of intraocular pressure of ∼2 mm Hg. Conclusions: Reproxalap may be a safe and effective alternative to topical corticosteroids for patients with NAU and other forms of ocular inflammation. These results represent initial clinical evidence of the importance of RASP in ocular inflammation and the applicability of RASP inhibition to immune modulation in ocular disease. Clinical trial (NCT02406209).

Keywords: anti-inflammatory; clinical studies; eye drops; inflammation; reactive aldehyde species; reproxalap; uveitis.

Conflict of interest statement

K.J.M. has served as a consultant to Aldeyra Therapeutics, and is a co-inventor on a patent assigned to Aldeyra Therapeutics.

D.C. is an employee of and an investor in Aldeyra Therapeutics.

D.S.C. has received grants from Mallinckrodt; is a consultant for Aldeyra, Dompé, and Mallinckrodt; has received honoraria from AbbVie and Mallinckrodt; and has received travel reimbursement from AbbVie, Dompé, and Santen.

C.S.F. has received financial support from Aciont, Alcon, Aldeyra, Bausch & Lomb, Clearside, Biomedical, Dompé,, Eyegate Pharma, Mallinckrodt, Novartis, pSivida, and Santen; is an investor in Eyegate Pharma; is a consultant for Aldeyra, Allakos, Bausch & Lomb, Eyegate Pharma, Genentech, Novartis, and pSivida; and has received fees for lectures and services for speaker bureaus for Alcon, Allergan, and Mallinckrodt.

J.S. has received financial support for consultancy and research from Aldeyra, AbbVie, and Bausch & Lomb.

T.C.B. is an employee of Aldeyra Therapeutics and an investor in Novadigm Therapeutics, Springbank Pharmaceuticals, Evoke Pharma, and Aldeyra Therapeutics, and is an inventor on patents for Aldeyra Therapeutics.

Figures

FIG. 1.

Patient disposition (CONSORT) for analysis populations. ITT, intention-to-treat.

FIG. 2.

Change from baseline anterior chamber cell (ITT population) was similar across groups. The last observation was carried forward for any patients who did not complete the trial. Error bars represent standard error of the mean (SE).

FIG. 3.

Reproxalap monotherapy and reproxalap + prednisolone therapy were statistically noninferior to corticosteroid monotherapy (ITT population). A mixed-effect model for repeated measures was performed at week 8 to assess anterior chamber cell grade reduction noninferiority at an upper bound of 0.5, as previously reported. Error bars represent 95% confidence interval (CI). ACC, anterior chamber cell.

FIG. 4.

Change from baseline in intraocular pressure (mm Hg, safety population) was numerically higher in the prednisolone group. Intraocular pressure elevations of ≥10 mm Hg were observed in 2 patients in the prednisolone group, whereas no elevations of ≥10 mm Hg were observed in the reproxalap or reproxalap + prednisolone groups. Error bars represent the standard error of the mean (SE). IOP, intraocular pressure.