After Phase III Disappoints, Inotek Looks to Fixed-Dose Combination

As Inotek Pharmaceuticals sifts through the disappointing Phase III top-line results for its lead clinical candidate trabodenoson and the 66% stock price slide that followed, the biopharmaceutical company is nonetheless looking ahead to development of a fixed-dose combination of trabodenoson with latanoprost that is ahead of schedule.

In a conference call with analysts the day the disappointing results from the MATrX-1 trial were released, Inotek president and CEO David Southwell said monotherapy trabodenoson “has always been something of a secondary priority for us relative to the fixed-dose combination [FDC _[1]],” because of a much bigger potential market upside for the latter.

Trabodenoson, a first-in-class, highly selective adenosine mimetic that targets the A1 subreceptor in glaucoma and augments trabecular meshwork outflow to lower intraocular pressure (IOP).

However, the order for the FDA review and approval of FDC up to now has relied on getting monotherapy trabodenoson out of the pipeline first. “I think we would need to talk to the FDA if we were to decide to develop the FDC without previously developing the monotherapy,” Southwell said in response to an analyst’s question.

But first, Southwell and his team at Inotek want to figure out why MATrX-1 failed to achieve its primary endpoint, which was statistically significant IOP reduction compared with placebo at all 12 time-points at days 14, 28, 42, and 84. IOP lowering at the 8 a.m. time-point was not statistically different with any trabodenoson dose versus placebo. The 6% (2000 mcg) once-daily dose did achieve statistically lower IOP reduction from baseline versus placebo.

“What we do know is that the reason we did not achieve the trial’s primary efficacy endpoint is that the placebo response was considerably larger than in the Phase II trial,” Southwell said. That placebo response was also more significant than that reported in a 2015 meta-analysis by Susan Raber of Pfizer and colleagues (J. Ocul. Pharmacol. Ther. 2015;31:189–97).

Rudolf Baumgartner, MD, Inotek executive VP and chief medical officer, told analysts the placebo response in MATrX-1 was 2–3 mm Hg greater than in the Phase II trial. Said Southwell, “We clearly need to better understand those results and particularly what drove the placebo response.”

Dr. Baumgartner noted one bright spot of MATrX-1 was that the effect of trabodenoson seemed to improve with time, going from lowering IOP 3.88 mm Hg at day 14 to 4.25 mm Hg at day 84. Added Southwell, “Many of the drugs in this market have tachyphylaxis, and the problem is that as you use them over time, the efficacy wanes.”

Also, the trial reported no serious adverse events or significant systemic side effects from monotherapy trabodenoson; no reports of drug-related eye pain, itching, or irritation; and hyperemia scores and incidence similar to placebo or timolol. Some 2.2% of patients discontinued the study because of trabodenoson-related adverse events. Southwell said the overall efficacy as well as the safety and tolerability profile demonstrated in MATrX-1 “bode well” for the Phase II FDC trial, from which Inotek anticipates a data readout at mid-year.

Since Inotek announced the top-line MATrX-1 results, its stock price has been on a rough ride, falling from $6.10 on December 30 to around $1.80 early in the week.

Southwell told the analysts that Inotek ended 2016 with $125 million in cash and marketable securities on hand. “We have a low structural burn rate with about 23 employees,” he said. “We’re well positioned financially to execute on our milestones.”

1. Raber S(1), Mandema JW, Li H, Nickens DJ. A model-based dose-response meta-analysis of ocular hypotensive agents as a drug development tool to evaluate new therapies in glaucoma. J Ocul Pharmacol Ther. 2015;31:189-97.