A pivotal phase 3 trial of trabodenoson ophthalmic suspension (Inotek Pharmaceuticals) for the treatment of patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) has failed to achieve its primary endpoint of superiority in the reduction of intraocular pressure (IOP) compared with placebo at all 12 time points. According to Inotek, this was partly due to a placebo response that was 2 to 3 mm Hg greater than that observed in a phase 2 study.
Trabodenoson is a first-in-class, selective adenosine mimetic targeting the A1 subreceptor. Trabodenoson lowers IOP by augmenting the eye’s natural function of the trabecular meshwork, the primary outflow pathway for aqueous humor and a site of pathology in glaucoma.
The MATrX-1 trial was a randomized, double-masked, placebo-controlled study of trabodenoson in 303 subjects diagnosed with POAG or OHT. The trial assessed the efficacy, safety, and tolerability of trabodenoson during three months of treatment. In addition, the study included a timolol 0.5% arm to validate the sensitivity of the patient population and to serve as an internal control. Three doses of trabodenoson ophthalmic suspension were administered: 3%/1,000 mcg once daily; 4.5%/1,500 mcg twice daily; and 6%/2,000 mcg once daily. The study enrolled patients with a diagnosis of POAG or OHT and with an IOP greater than or equal to 24 mm Hg and less than or equal to 34 mm Hg.
The study’s primary endpoint was the reduction in IOP with trabodenoson compared with placebo on days 28, 42, and 84 and at four time points during each of these days: 8 a.m., 10 a.m., 12 p.m., and 4 p.m. The 8 a.m. time point did not achieve statistical separation with any trabodenoson dose. This was primarily due to an unexpectedly high placebo response compared with that observed in a phase 2 study published in 2015.
The 6%/2,000 mcg QD dosage of trabodenoson was statistically superior to placebo on days 14, 42, and 84, and was marginally superior on day 28. The daily IOP reduction from diurnal baseline at three months for this dosage was 4.25 mm Hg compared with 2.38 mm Hg for placebo and 5.29 mm Hg for the timolol 0.5% twice-daily control arm.
No significant safety or tolerability events were reported. Four subjects (2.2%) discontinued the study because of treatment-related adverse events.
Source: Inotek Pharmaceuticals; January 3, 2017.