Missing the secondary endpoint in the phase III trial with NBI-98854 did little to dampen enthusiasm for Neurocrine Biosciences Inc.'s small-molecule vesicular monoamine transporter 2 (VMAT2) inhibitor against tardive dyskinesia (TD), which achieved a resounding tackle of the primary endpoint: change from baseline in the Abnormal Involuntary Movement Scale (AIMS) at the sixth week in the 80 mg once-daily dosing group compared to placebo, as judged by blinded video raters.
That secondary target, Clinical Global Impression of Change for 40 mg and 80 mg doses, is "a fairly standard blunt instrument," said San Diego-based Neurocrine's chief medical officer (CMO) Chris O'Brien during a conference call with investors. "Most psychiatrists are very familiar with the AIMS," the primary-endpoint measure, and "they use it as a safety scale," he said. "But the reality is, when you see a video of a patient before and after, that's more powerful than any of these scales. And, as we do our market research, the psychiatrists say, 'Show us that you have a positive study. Get the drug on the market, and we will use it.'"
Such is the plan for Neurocrine, which aims to submit a new drug application (NDA) for NBI-98854 in TD, a movement disorder that arises from the use of antipsychotic medications, in the first quarter of next year.
Called Kinect 3, the latest experiment included moderate to severe TD patients with underlying schizophrenia, or disorders that included schizoaffective, bipolar and major depressive. Specifically, video raters found a reduction of 3.1 points more than placebo on the AIMS score. An earlier study, Kinect 2, reported a 2.4-point difference from placebo. Neurocrine officials on the conference call suggested that they saw efficacy as early as two weeks, improving to the six-week mark. At the 40 mg once-daily dose there was a significant improvement of 1.8 points over placebo (p = 0.0021) on an intent-to-treat basis. "The data appear better than data reported by Teva Pharmaceuticals Industries Ltd. from its Arm-TD phase III evaluating Austedo, in which only a 1.4 point difference was observed," in the view of Jefferies analyst Biren Amin.
Petah Tikva, Israel-based Teva's candidate, also known as SD-809, is a deuterium-substituted analog of tetrabenazine that also inhibits VMAT2, and the firm has already filed for approval in the lead indication: chorea related to Huntington's disease. In the spring, Teva gained the drug by way of its $3.2 billion tender offer for all of orphan-drug firm Auspex Pharmaceuticals Inc.'s outstanding shares at $101 each. Teva estimated the La Jolla, Calif.-based firm's drug could be worth "$2 billion and beyond." (See BioWorld Today, March 31, 2015.)
'BEST IN CLASS'
Leerink Partners analyst Paul Matteis was more circumspect about Neurocrine, noting that "cross-trial comparisons hold limitations, especially without full results from either study." Still, the top-line efficacy data from Neurocrine's drug "compare nicely" with Teva's, he said, and estimated a 90 percent chance of approval for the former's candidate in TD. "Comparisons are not apples-to-apples, as Teva assessed patients at 12 weeks," he pointed out. O'Brien addressed the difference during the conference call. "Obviously, we discussed this at length with the FDA," he said. "They were very happy with the trial design. And the trial is designed to continue to look at the aims in TD during the extension phase of the trial out to one year. So, we will be able to talk about persistence of effect, and address that directly."
Kinect 4, the one-year, open-label safety study intended to supplement the safety database, continues to enroll patients. Neurocrine expects the safety records for the compound, which has been designated a breakthrough therapy by the FDA, will include more than 1,000 patients at the time of the NDA filing. Leerink's Matteis also said that, "mechanistically, it is unclear to us why the two products would have differentiated safety profiles as they both inhibit dopamine release through VMAT2, and thus the varying effects may be due to patient populations, chance, timing of evaluation or study design." Upside in that realm, however, "could improve perception of [Neurocrine's candidate] in the marketplace, important for the company, given the difficulties competing with Teva's commercial central nervous system franchise," in his view.
"We haven't given any details on specific adverse-event frequencies," CMO O'Brien said. "The safety profile was comparable across treatment groups. That is, placebo, 40 mg and 80 mg look very comparable. And our data safety monitoring board has been very clear that they are not seeing safety signals that call out one dose over another dose. So far, that's been quite good. We do plan on filing the NDA with both the 40 mg and the 80 mg doses. Obviously, how the FDA wants us to approach that is part of their review and our label discussions."
Cowen and Co. analyst Phil Nadeau seemed to agree with his Wall Street peers.
"We believe that, with these data, NBI-98854 has established a best-in-class profile in TD, and we expect its strong efficacy, once daily dosing, no titration requirement and a benign safety profile to be very appealing to this challenging patient population," he wrote in a report, with a nod to better AIMS scores and more convenience: once-daily compared to twice-daily dosing.
Shares of Neurocrine (NASDAQ:NBIX) closed Thursday at $43.60, up $4.67, or 12 percent.