Hailed last year by Cowen and Co. as "one of the most unbalanced risk/reward opportunities we have ever seen" in a good way Inotek Pharmaceuticals Corp.'s eye drop trabodenoson for glaucoma won the go-ahead from U.S. regulators to begin phase III trials. Wall Street rejoiced, pushing shares (NASDAQ:ITEK) up 194 percent, or $10.14, to close Thursday at $15.37.
CEO David Southwell told BioWorld Today that the first of two pivotal experiments, due to start in the fourth quarter of this year, is unique because it's powered against placebo, "which allows us to firstly do a much more efficient study; our phase II results showed a lot of statistical significance against placebo. But the second thing it allows us to do is have three different doses of trabodenoson in there, [given once per day and twice per day], so we can really get a lot more information than we could if it were a noninferiority" experiment, as explained to the FDA during a recent end-of-phase-II meeting. But a timolol arm will be included, too.
"We are going to be able to look at our effect compared to timolol, but we wanted to statistically compare ourselves to placebo," Southwell said. "Not because of the strength of timolol, but because it allows us to reduce the number of total patients in the study and increase the number of doses. Ultimately, if we're marketing trabodenoson, we want to be able to talk about how it does in the marketplace." Involving timolol "validates the study, because there's a very well established efficacy profile with timolol in phase III studies," he said, and "gives us the opportunity to talk about how we do vs. timolol" if trabodenoson wins approval.
Reduction of intraocular pressure (IOP) is the primary efficacy endpoint of the five-arm trial. Data in 2016 will inform the design of the second phase III study. A separate safety trial will run "alongside the clinical trials, and that shouldn't be a gating factor to submitting the new drug application," he said. The overall program will consist of three trials and 1,300 patients.
Trabodenoson, an adenosine mimetic, is all about the molecular refresh-work of the trabecular meshwork, "really the primary regulator of eye pressure," Southwell said. "We're not changing the biology of the eye in any way," but stimulating a natural process to allow outflow from the meshwork. In phase II trials, trabodenoson gained a dose-related response for IOP-lowering in ocular hypertension as well as primary open-angle glaucoma. After 14 days of treatment, the 200-mg and 500-mg doses turned up a statistically significant reduction (p<0.05) in IOP relative to the matched placebo group. After 28 days, the 500-mg benefit held relative to placebo, in the range of other glaucoma therapies. Across all studies, the efficacy of trabodenoson has stayed consistent, with no waning effect and the IOP dip steady across subpopulations. The drug has been well tolerated, with no serious adverse events.
Glaucoma, Southwell noted, is "not just about eye pressure. You have a decline in the retinal ganglion cells," and trabodenoson may protect the retinal ganglion cells themselves by way of another mechanism. "Of course, the data are all very early" on that, he said, and consist of findings from animal studies. Asked about the ethics of using a placebo control in the human trials, he pointed out that glaucoma "is a very slow moving disease, so it takes a while for the IOP to ramp up. For that reason we think it's unlikely we're going to have a problem. If [patients] were to see an increase in eye pressure, we could always pull them out of the study." In the one-month, phase II study with placebo, "we had one dropout on the placebo arm. We certainly think [the phase III] is ethical and doable," he said.
Research Triangle Park, N.C.-based Aerie Pharmaceuticals Inc., the other glaucoma eye drop phase III player, came a cropper in April with Rhopressa, its phase III Rho kinase inhibitor. Aerie's Rocket 1 study missed its primary efficacy endpoint of noninferiority in lowering IOP as compared to twice-daily timolol. That's when Cowen issued its upbeat research report on Inotek. Analyst Ken Cacciatore wrote that his firm's glaucoma consultants "have been steadfast in their feedback that novel mechanisms of action are a major unmet need in this debilitating condition. Specifically, they note that roughly half of all glaucoma patients fail on monotherapy (typically first-line treatment is with a prostaglandin) and the add-on therapies that are currently available only provide a modest additional reduction in IOP with notable side effects. As a result, our consultants have been adamant that if a novel mechanism of action for glaucoma was available that provided comparable efficacy to current second-line agents along with a clean safety profile and we believe trabodenoson has all of these attributes that the product would be 'extremely compelling.'" (See BioWorld Today, April 27, 2015.)
DEVICES IN THE GAME
Last month, Aerie said the FDA agreed to a change of the primary endpoint for Rocket 2, the second phase III registration trial, which had been designed similarly to Rocket 1. The firm is switching the primary endpoint range to include patients with baseline IOPs ranging from above 20 mmHg to below 25 mmHg. The former range was above 20 mmHg to below 27 mmHg, which is now the secondary endpoint.
"As often happens in the biotech and pharmaceutical business, it's more perhaps perceived as a tug of war than an actual tug of war" between Inotek and Aerie, Southwell said, pointing to the different mechanisms of action. Piper Jaffray analyst Joshua Schimmer, at the time of the Aerie failure, saw potential for both drugs. "While many investors had believed that Rhopressa was high probability for success whereas Inotek's trabodenoson is low probability for success, we've wondered whether the differences between the two drugs was as much a reflection of trial design as opposed to true efficacy," he wrote in a research report. "We still think there is a path forward for Rhopressa, in the same way that we think there is a path forward for trabodenoson."
Southwell acknowledged that compliance rates with glaucoma eye drops outside of closely monitored trials is "remarkably low," probably because of the side effects, a problem Inotek hopes to evade with trabodenoson's solid profile in that regard. Device companies also have strategies. "Of course, with devices, you're probably talking about a later stage of glaucoma," he said. "On the other hand, the device manufacturers are hoping the pricing will be good," since the devices would be used in sicker patients. One in development is a punctum plug that elutes prostaglandin inside the eye, thus eliminating the compliance issue. Ocular Therapeutix Inc., of Bedford, Mass., is enrolling patients in a phase IIb study with the travoprost punctum plug.
Also in devices, Laguna Hills, Calif.-based Glaukos Corp. markets the Istent Trabecular Micro-Bypass Stent for use in conjunction with cataract surgery for the reduction of intraocular pressure in adult patients with open-angle glaucoma. The smallest medical device ever approved by the FDA, it's inserted through the small corneal incision made during cataract surgery and placed into Schlemm's canal, a circular channel in the eye that collects aqueous humor and delivers it back into the bloodstream. Once inserted, the Istent improves aqueous humor outflow while fitting naturally with Schlemm's canal, Glaukos said. The company went public in June, raising $118 million. Shares of the firm (NYSE:GKOS) jumped 73 percent on the first day of trading.
Glaukos' shares closed Thursday at $32, up $1.22.