Inotek Pharmaceuticals announced topline results of MATrX-1, the first pivotal phase 3 trial of trabodenoson for the treatment of primary open-angle glaucoma or ocular hypertension. The trial did not achieve its primary endpoint of superiority in reduction of in IOP compared with placebo at all 12 time points. This was, in part, due to a placebo response that was 2-3 mmHg greater than that observed in phase 2, according to a company news release.
Trabodenoson, the company’s lead clinical candidate, is a first-in-class, highly 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.
“We are disappointed that the primary endpoint of superiority at all 12 time points was not achieved,” David P. Southwell, President and Chief Executive Officer of Inotek, said in the news release. “This result was driven primarily by the unexpectedly stronger placebo response at the 8AM time point. However, MATrX-1 did achieve several clinically meaningful secondary endpoints - the 6% dose was significant versus placebo in the daily IOP change from diurnal baseline at all days tested. Additionally, an analysis of responders (subjects with IOP reduction of 5mmHg or greater from baseline) indicated a statistically higher proportion of responders in the 6% trabodenoson group than the placebo group at all visits. The safety, tolerability and low discontinuation rate in MATrX-1 continues to suggest that trabodenoson is an active molecule with a unique safety profile. Later this quarter, we expect to receive additional data beyond the topline results reported today. Once we have the additional data, we will determine next steps in the trabodenoson monotherapy program.”
The primary endpoint of the MATrX-1 trial was the IOP reduction of trabodenoson compared to that of placebo on days 28, 42, and 84 and at four time points during each of these days: 8AM, 10AM, 12PM, and 4PM. The 8AM time point did not achieve statistical separation with any trabodenoson dose. This was primarily due to an unexpectedly high placebo response compared to that observed in phase 2, as well as a published meta-analysis by Raber et al.1
The 6%/2000 mcg QD dose of trabodenoson was statistically superior to placebo at days 84, 42, 14 and marginally superior at day 28. The daily IOP reduction from diurnal baseline at 3 months for this dose was 4.25 mmHg compared to 2.38 mmHg for placebo, and 5.29 mmHg for the timolol 0.5% twice daily control arm. The normal response observed with the timolol control arm supports that the trial was properly conducted.
There were no significant safety or tolerability events reported. The safety profile of trabodenoson was comparable to placebo. Notably, there was minimal drug-related hyperemia. Only 4 subjects (2.2%) discontinued the trial due to a treatment-related adverse event.
“The results of the MATrX-1 trial demonstrate that trabodenoson, operating through a novel mechanism of action, actively lowers IOP with a tolerability profile that, remarkably, was similar to that observed in the placebo arm,” Rudolf Baumgartner, MD, Executive Vice President and Chief Medical Officer of Inotek, said in the news release.
“Looking ahead, 2017 is an important year for the trabodenoson development program. We will wait for the full results from MATrX-1 to better understand the behavior of the placebo arm. We look forward to the results of the FDC Phase 2 trial, which is substantially enrolled and for which we expect to report top-line data mid-year," Mr. Southwell.
MATrX-1 Phase 3 Trial Design
MATrX-1 was a phase 3 randomized, double-masked, placebo-controlled trial of trabodenoson in 303 subjects diagnosed with POAG or OHT. MATrX-1 assessed the efficacy, safety and tolerability of trabodenoson over 3 months of treatment. The primary endpoint was reduction of IOP as compared to the placebo treatment arm. In addition, the study contained a timolol 0.5% arm to validate the sensitivity of the patient population and serve as an internal control. IOP was measured at four time points during the day: 8AM, 10AM, 12PM, and 4PM on days 14, 28, 42 and 84. Three doses of trabodenoson ophthalmic suspension were administered: 3%/1000 mcg once daily, 4.5%/1500 mcg twice daily, and 6%/2000 mcg once daily. The trial enrolled patients with a diagnosis of POAG or OHT and an IOP greater than or equal to 24 mmHg and less than or equal to 34 mmHg.