An experimental glaucoma drug developed by Inotek Pharmaceuticals Corp. to augment the eye’s natural method of reducing intraocular pressure (IOP) failed to prove itself better than a placebo at all 12 time points of the pivotal phase III study Matrx-1. The shortfall for trabodenoson, Inotek’s lead candidate, crushed company shares (NASDAQ:ITEK), which fell 71.3 percent to close Tuesday at $1.75.
Further analysis of the failure is underway as the company determines next steps for the monotherapy program, and currently holds plans for a second pivotal trial, Matrx-2, and a long-term safety trial, Matrx-3.
“Phase III results always contain unexpected elements which teach us about the compounds we are developing, and the Matrx-1 trial is no exception,” said David Southwell, president and CEO of the Lexington, Mass.-based company.
The unexpected element in Matrx-1 turned out to be a placebo response that Southwell said was “considerably larger” than what the company had seen in its phase II study as well as what was observed in a meta-analysis of IOP-lowering monotherapy studies published in May 2015, he said. (See BioWorld Today, July 24, 2015.)
Double-masked and placebo-controlled, Matrx-1 tested three doses of trabodenoson in 303 participants diagnosed with either primary open-angle glaucoma or ocular hypertension, with the primary endpoint of reduction of IOP vs. placebo. In addition, the study contained a timolol 0.5 percent arm to validate the sensitivity of the patient population and to serve as an internal control. IOP was measured at four time points during the day: 8 a.m., 10 a.m., 12 p.m. and 4 p.m. on days 14, 28, 42 and 84.
While no significant safety or tolerability events were reported, the study of the adenosine mimetic yielded three unexpected findings relative to the company’s phase II trabo test, said Inotek’s chief medical officer, Rudolf Baumgartner.
During a conference call held to discuss the outcome, Baumgartner said that in terms of IOP — generally measured by millimeters of mercury (mmHg) — the magnitude of the placebo response was about 2 mm to 3 mm greater than in phase II and the average as reported in the Raber meta-analysis. Furthermore, investigators did not see a direct relationship between efficacy and the amount of drug that the eye received, he said. A lack of perceivable separation between placebo and trabodenoson at the 8 a.m. time point was especially surprising, he said, since the phase II study had shown separation at that time point.
“Unexpectedly, the dose with the most amount of drug delivered to the eye within a 24-hour period, the 4.5 percent [twice-daily] dose, was the least effective, while the 6 percent dose was statistically equivalent to placebo at 8 a.m.” he said. Trabodenoson-treated patients also showed a significantly lower IOP than placebo at 10 a.m. and 12 p.m., with a marginally significant lowering at 4 p.m.
“As a whole, these data indicate that the drug is certainly active and well-tolerated, but that the inter-relationship between dose and dosing interval needs to be better understood,” Baumgartner said.
With the monotherapy data in hand, the company is now looking forward to the anticipated midyear readout of a phase II study evaluating several fixed-dosed combinations of trabodenoson and latanoprost, a prostaglandin analogue. The hope there is to identify a fixed-dose combination product with better efficacy than latanoprost alone, but with a similar or more favorable safety and tolerability profile. The trial is almost fully enrolled, with more than 90 percent of patients screened, said Southwell.
Inotek ended 2016 with about $125 million in cash and marketable securities and has “a low structural burn rate,” Southwell said, with about 23 employees. While that foundation will carry the company ahead, Piper Jaffray analyst Joshua Schimmer appeared to think the company had lost a fair bit of shine, downgrading his rating on company shares to neutral, “until we have a clearer path towards clinical, regulatory and commercial success.”