Over the past few days at the 128th Annual Meeting of the American Academy of Ophthalmology (AAO) 2024 in Chicago, the potential of brepocitinib for treating non-infectious intermediate, posterior, and panuveitis was discussed. Six-month data from Priovant Therapeutics’ Phase II trial, NEPTUNE (NCT05523765), was presented, marking brepocitinib’s seventh Phase II trial.

Brepocitinib attracted a notable amount of attention at the AAO meeting for its first-in-class novel dual-inhibitor mechanism of action in the non-infectious uveitis (NIU) field, simultaneously providing a more convenient option for patients due to being a once-daily oral agent. Brepocitinib acts in a unique manner to inhibit tyrosine kinase 2 (TYK2) and JAK protein 1 (JAK1) signaling. Given the pathogenesis of NIU, which is variable and intricate, involving IL-2, IL-6, IL-10, IL-12, IL-23, and INF-y6, brepocitinib may provide more favorable efficacy in patients of this sub-indication.

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In NEPTUNE, patients with active non-infectious intermediate, posterior, or panuveitis were randomized into two groups, brepocitinib 45mg once daily (n=17), and brepocitinib 15mg once daily (n=9), over the course of 52 weeks. At baseline, patients were also administered prednisone 60mg for two weeks, followed by a tapering regimen over six weeks. Treatment failure was the primary efficacy endpoint of the study, defined by worsening best corrected visual acuity (BCVA), inflammation, and the emergence of new inflammatory lesion between Weeks 6 and 24.

In results presented on Sunday by Dr. Quan Dong Nguyen, MD, MSc, FARVO, FASRS, Byers Eye Institute, Stanford University School of Medicine, significant efficacy findings were reported. At six weeks, despite its fast-tapering regimen compared to historical controls, brepocitinib lowered treatment failure in a dose-dependent manner. Compared to the prespecified historical placebo control, which showed 80% treatment failure, the brepocitinib 15mg group had a significantly lower treatment failure rate of 44% (p <0.05), while the brepocitinib 45mg group had a significantly lower treatment failure rate of 29% (p <0.0001). Additionally, components of treatment failure were also reduced by brepocitinib in a dose-dependent manner. Notably, the percentage of patients experiencing a worsening of BCVA by more than five letters was 67% in the brepocitinib 15mg study arm, and 24% in the brepocitinib 45mg study arm. The percentage of vitreous hemorrhage (VH) above grade 1 was 33% in the brepocitinib 15mg study arm and 12% in the brepocitinib 45mg study arm.

By Week 24, posterior segment inflammation was reduced by 0.5 fluorescein angiography (FA) score in the brepocitinib 15mg group and by 4.4 FA score in the brepocitinib 45mg group, reflecting a dose-dependent effect. In terms of central

subfield thickness (CST), the brepocitinib 45mg group achieved a 15.4% mean change from baseline through to Week 24, establishing sustained CST improvement; within this group, patients with baseline macular edema experienced the largest improvement in CST, as well as resolution of macular edema that was present at baseline. As for patients without macular edema at baseline, none went on to develop macular edema by Week 24.

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As for the safety profile of brepocitinib, in general, the treatment was tolerated well by patients. No thrombolytic events, major adverse cardiovascular events (MACE), malignancies, or deaths were reported. As for severe adverse events (SAEs), one was reported for hypersensitivity of moderate severity within the brepocitinib 15mg study arm, which was treated with oral diphenhydramine, and another SAE was reported for costochondritis. As for treatment-emergent adverse events (TEAEs), the most commonly reported were rash and arthralgia; other TEAEs reported were mild or moderate and not related to uveitis.

Key opinion leaders (KOLs) interviewed by GlobalData have highlighted that there is an unmet need for non-steroid therapies particularly for uveitis concerning the posterior segment of the eye.

All in all, brepocitinib showcased that active NIU patients had clinically meaningful treatment failure reductions in a dose-dependent manner by Week 24. Reduction in posterior segment inflammation was also dose-dependent, with brepocitinib 45mg attaining a clinically meaningful change in FA score. Looking ahead, Priovant Therapeutics has enrolled its first patients in CLARITY, its Phase III trial for brepocitinib. Should NEPTUNE results be emulated in CLARITY, brepocitinib 45mg has the potential to become a first line of therapy for non-infectious intermediate, posterior, and panuveitis patients once it reaches the market.

According to GlobalData’s Pharma Intelligence Center, for non-infectious intermediate, posterior, and panuveitis, worldwide, there are three Phase III candidates, two Phase II candidates, and one Phase I candidate.