A new small molecule DHODH-inhibitor [KIO-100 (PP-001)] targeting activated T cells for intraocular treatment of uveitis - A phase I clinical trial

Abstract

Uveitis is a T cell-mediated, intraocular inflammatory disease and one of the main causes of blindness in industrialized countries. There is a high unmet need for new immunomodulatory, steroid-sparing therapies, since only ciclosporin A and a single TNF-α-blocker are approved for non-infectious uveitis. A new small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme pivotal for de novo synthesis of pyrimidines, has a high potency for suppressing T and B cells and has already proven highly effective for treating uveitis in experimental rat models. Systemic and intraocular application of KIO-100 (PP-001) (previously called PP-001, now KIO-100) could efficiently suppress rat uveitis in a preventive as well as therapeutic mode. Here we describe the outcome of the first clinical phase 1 trial comparing three different doses of a single intraocular injection of KIO-100 (PP-001) in patients with non-infectious posterior segment uveitis. No toxic side effects on intraocular tissues or other adverse events were observed, while intraocular inflammation decreased, and visual acuity significantly improved. Macular edema, a sight-threatening complication in uveitis, showed regression 2 weeks after intraocular KIO-100 (PP-001) injection in some patients, indicating that this novel small molecule has a high potential as a new intraocular therapy for uveitis.

Clinical trial registration: [https://www.clinicaltrials.gov/ct2/show/NCT03634475], identifier [NCT03634475].

Keywords: clinical phase 1 trial; experimental autoimmune uveitis; humans; intravitreal therapy; macular edema; rat; uveitis; visual acuity.

Conflict of interest statement

Authors FO, SS, and RS-Z were employed by Kiora Pharmaceuticals Inc. (previously Panoptes Pharma GmbH). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Thurau, Deuter, Heiligenhaus, Pleyer, Van Calster, Barisani-Asenbauer, Obermayr, Sperl, Seda-Zehetner and Wildner.

Figures

FIGURE 1

Structure of KIO-100 (PP-001). See also compound 13 in Leban et al. (16).

FIGURE 2

Development of visual acuity in the three treatment groups (n = 4) from baseline until the end of the study at day 28, assessed at the respective visits. “All patients” shows the means of visual acuity ± SE from all patients of the different treatment groups. Note that decreasing Log[MAR] values represent increasing visual acuity. Asterisks represent significant (p ≤ 0.05) differences to baseline.

FIGURE 3

Intraocular pressure (IOP) from baseline until the end of the study at day 28, assessed at the respective visits. Mean mmHg ± SE is shown for all patients from the different treatment groups.

FIGURE 4

Inflammation parameters according to the SUN grading from baseline until the end of the study at day 28, assessed at the respective visits. (A) Cells in the anterior chamber (AC cells). (B) Vitreous haze. Mean grading score of AC cells ± SE (A) and mean vitreous haze scores ± SE (B) are shown for all patients from the three different dosing groups at each visit. According to the SUN grading scheme for AC cells and vitreous haze six grading steps are defined (0+, 0.5+, 1+, 2+, 3+, and 4+) (19, 20).

FIGURE 5

Central retinal thickness (CRT) from baseline until the end of the study at day 28, assessed at the respective visits. CRT measurements were extracted from automated standard OCT (optical coherence tomography) of the central fovea of the macula. CRT is depicted for each visit of all patients pooled from the three different dosing groups.

FIGURE 6

Optical coherence tomography (OCT) images. The upper panel shows macula of patient # 06-02 at baseline (A) and on day 28 (B) after intraocular injection of 0.6 μg KIO-100 (PP-001). Note a clinically meaningful reduction of cystoid macular edema (CME) in the region of the macula. In the lower panel the macula of patient # 05-01 is shown at baseline (C) and at day 14 (D) after injection of 1.2 μg of KIO-100 (PP-001). In this case the initial size of CME spaces was much smaller, but after injection the CME has disappeared completely.

FIGURE 7

Visual field testing was performed at baseline, days 7 and 28. Mean deviation from normal is shown for each visit of all patients pooled from the three different dosing groups. All patients had loss of visual field sensitivity at baseline due to pre-existing destruction of previous chronic uveitis. In the follow up were no additional losses of more the 2 dB in a single patient. At day 28 the average visual field sensitivity had increased slightly, probably in part by training effects.