Sepetaprost Is Safe, Effective for IOP Reduction in POAH and OHT

David L. Wirta, MD

A 0.002% concentration of sepetaprost (DE-126) demonstrated promising reductions in intraocular pressure (IOP) for patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT), according to findings from a phase 2b dose-finding study presented at the 2019 American Academy of Ophthalmology Annual Meeting.

The 0.002% concentration sepetaprost resulted in a ≥20% reduction in IOP for 84% of treated patients, which compared favorably to latanoprost 0.005% (84%). Overall, 61% of patients treated with sepetaprost 0.002% had a reduction in IOP to below ≤18 mmHg, compared with 70% in the latanoprost 0.005% group. However, a formal statistical analysis comparing arms was not conducted as part of the dose finding study.

"For each sepetaprost concentration, the IOP-lowering effect was observed at the first follow-up visit (week 1) and remained stable throughout the study," lead author David L. Wirta, MD, from the Eye Research Foundation in Newport Beach, CA, wrote in a poster presented at the AAO meeting. "A positive dose-response relationship was generally observed across the 3 lower concentrations of sepetaprost. Sepetaprost 0.003% did not result in greater IOP lowering than sepetaprost 0.002%."

Sepetaprost is a prodrug that is hydrolyzed by esterases to its active metabolite. The agent lowers IOP through a dual mechanism of action, hitting both the FP and EP3 receptors simultaneously, unlike other prostaglandin analogs that operate primarily through the FP receptor. Early data has suggested this dual mechanism could improve IOP reduction.

In the phase 2b study, 241 patients were randomized in a 2:2:2:2:2:1 ratio to receive sepetaprost at 1 of 4 dose levels ranging from 0.0005% to 0.003%, latanoprost 0.005%, or placebo with a switch to sepetaprost after 6 weeks. Twenty-two patients were randomized to the placebo arm, with 43, 43, 44, and 45 in sepetaprost 0.0005%, 0.001%, 0.002%, and 0.003% arms, respectively. The latanoprost group contained 44 patients. Patients were evenly enrolled in Japan (n = 114) and the United States (n = 127).

Patient characteristics were well balanced across groups, with patients ranging in mean age from 61.0 to 65.5 years. The diagnoses were fairly evenly split 50:50 between POAH and OHT across groups. IOP was similar across arms at approximately 24 mmHg, and the mean central corneal thickness was also similar between groups at 549.1 to 555.6 μm. A third of patients had glaucomatous optic nerve findings. A third of patients had receive no prior therapies, and half had received prior prostamide or prostaglandin analog treatment.

A positive dose response was seen across lower doses of sepetaprost, which stopped at the 0.003%. Overall, the 0.002% dose showed greater IOP lowering than the 0.003%; moreover, the 0.002% dose resulted in the numerically lowest IOP of the 4 four sepetaprost concentrations. In this group, the IOP dropped below 17 mmHg, which was similar to latanoprost. In the placebo group, the IOP dropped to approximately 22 mmHg.

The mean change from baseline at week 6 measured at 5 pm for the sepetaprost 0.002% concentration was -7.0 mmHg (-29.4% change from baseline) as compared with -2.7 mmHg in the placebo group (-11.1% versus baseline) and -6.8 mmHg in the latanoprost arm (-26.1% change from baseline). For the other concentrations, the change from baseline was -5.9 mmHg, -5.7 mmHg, and -6.2 mmHg for the 0.0005%, 0.001%, and 0.003% concentrations, respectively.

"In both Japan- and USA-based patients, sepetaprost 0.002% was identified as the topical dose among 4 concentrations assessed with respect to IOP lowering," Wirta et al wrote in their poster. "The magnitude of this reduction was similar to that observed for latanoprost 0.005% and month 4 and significantly greater than that of placebo at week 6."

Most adverse events (AEs) seen in the study were mild in severity. Overall, the incidence of AEs was lower in the sepetaprost 0.002% arm compared with latanoprost 0.005%, with 34.1% having an AE in the sepetaprost group compared with 50% in the latanoprost 0.005% arm. However, the rate of AEs was similar between the 0.003% sepetaprost group (50.8%) and the latanoprost group (50%). Serious adverse reactions were only observed in the placebo arm, prior to switching to sepetaprost.

"Most AEs were mild in severity; AE incidence was lower with the sepetaprost concentrations of 0.0005%, 0.001%, and 0.002% compared with latanoprost 0.005% and sepetaprost 0.003%," Wirta et al wrote in their poster. The next steps for the agent are unclear.

Wirta D, Kuwayama Y, Lu F, et al. Dose-Finding Study of Sepetaprost Ophthalmic Solution in Patients With POAG or OHT: The Phase 2b ANGEL Study. Presented at: 2019 AAO Annual Meeting, San Francisco, CA, October 12-15, 2019.