In the wake of Alcobra Ltd.'s FDA-mandated clinical hold on the phase III study with metadoxine extended release in adults with attention deficit hyperactivity disorder (ADHD), Supernus Pharmaceuticals Inc. – which chalked up positive data Tuesday in a phase IIb trial with SPN-812 – finds itself in what CEO Jack Khattar called a "horse race" with Sunovion Pharmaceuticals Inc., recently the bearer of positive data from a pivotal trial with dasotraline in children ages 6 to 12.

Viloxazine hydrochloride, the nonstimulant active ingredient in SPN-812, is considered a new chemical entity because it's never been developed in the U.S. market, though it is available outside the U.S. as an antidepressant.

"We are building a strong intellectual property portfolio, with expirations that we expect to be in the 2029-2033 time frame" in ADHD, Khattar said during a conference call with investors. "As far as our plans on the antidepressant [side go], actually that is SPN-809, which you will see in our pipeline. We have always had that, as far as future plans go, to develop that product as an antidepressant. It hasn't been a top, top priority. However, we actually have been making significant progress in moving SPN-809 [through] our pipeline by doing all the work we've been doing on SPN-812, because clearly it is the same molecule: viloxazine. We've done a significant amount of work on the active pharmaceutical ingredient synthesis, on the formulations, on all the preclinical work. All that will apply to SPN-809 as well – mind you, obviously, in a different indication.

"So we've been progressing 809 at the same time, basically, as we are progressing 812. Whether we will commercialize an antidepressant . . . that will probably not be the case for us," and the program will likely be out-licensed, he said.

Meanwhile, Rockville, Md.-based Supernus is proceeding to an end-of-phase II meeting with the FDA after a positive dose-ranging experiment that tested SPN-812, also in children 6 to 12. The phase IIb trial hit the primary endpoint, demonstrating that SPN-812, a selective norepinephrine reuptake inhibitor, at daily doses of 400 mg, 300 mg and 200 mg, achieved a statistically significant improvement in the symptoms of ADHD from baseline to the end of the study, as measured by the ADHD Rating Scale-IV. The effort was a randomized, double-blind, placebo-controlled, multicenter trial, with each treatment administered orally once a day over five weeks, after a three-week titration phase. All doses tested in the trial were well-tolerated.

"Regarding which patient population [to pursue] in ADHD, you always have to do pediatric at minimum," Khattar said. "You can't even develop a product for adults without pediatric. Clearly, we will be going after pediatric and definitely after adult as well."

He said the firm intends to start phase III trials next year, if talks proceed satisfyingly with the FDA.

FASTER ONSET KEY IN KIDS

Supernus has something of a hurdle as it faces the regulatory scrutiny given to Strattera (atomoxetine), from Indianapolis-based Eli Lilly and Co., which brings effects related to selective inhibition of the pre-synaptic norepinephrine transporter to treat ADHD and therefore works similarly – and carries a black-box warning about suicidal thoughts in children and teenagers. "Given that viloxazine may be considered as a similar drug with similar kind of mechanism of action, that is a possibility" for the Supernus treatment as well, Khattar conceded.

"I don't know yet for sure. We will see how that pans out as we develop the product and as we generate more data in the phase III trial." But SPN-812 "doesn't have any of the other side effects or issues [that] Strattera has, like liver damage [and] cardiac issues" such as blood-pressure fluctuations, he said. "We would still have a much cleaner side effect profile, even if we end up with a black-box warning."

Jefferies analyst David Steinberg said SPN-812 "has the potential to fill an important ADHD market gap," and estimated peak sales beyond $250 million. "The limitations of stimulant therapies for ADHD [such as Vyvanse (lisdexamfetamine dimesylate, Shire plc] have been well-elucidated and [the Supernus candidate] therefore has the potential to become the leading branded nonstimulant ADHD drug (8 percent of ADHD prescriptions are nonstimulants), if successfully developed," he wrote in a report. "Key possible benefits include a faster onset of action (efficacy as early as one to two weeks vs. about five weeks for Strattera), which is particularly important in children. And it would have no Drug Enforcement Administration scheduling constraints, which could assist uptake in what will be a largely genericized market segment later this decade."

Intuniv (guanfacine, Shire plc) is already generic and Strattera is expected to meet the same fate next year, Steinberg noted, adding that the safety profile may ultimately save SPN-812 from a black-box warning. His peak-sales estimate "could prove conservative, as second to market Intuniv reached $166 million during its first full year of promotion."

Alcobra, of Tel Aviv, Israel, received formal word last week of the clinical hold on its ADHD study called MEASURE because of electrophysiological neurologic findings in previously submitted long-term animal studies with metadoxine, a selective antagonist to the 5-HT2B receptor, a member of the serotonin receptor family. The FDA letter did not reference any clinical safety data observed in the MEASURE study or in previous human studies with the candidate, but U.S. regulators recommended that Alcobra schedule a meeting to discuss a plan to collect more human safety data in its development program. MEASURE is a multicenter, randomized, double-blind, placebo-controlled test of MDX (1,400 mg daily) for 10 weeks compared with placebo in adults.

Marlborough, Mass.-based Sunovion's dasotraline, a dopamine and norepinephrine reuptake inhibitor, last month yielded results from the SEP360-202 phase II/III trial, a six-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, fixed-dose safety and efficacy experiment. The study evaluated once-daily dasotraline (2 mg/d and 4 mg/d dose arms) in 342 children, with a primary efficacy endpoint of change from baseline to the sixth week in the ADHD Rating Scale-IV. The 4-mg dose arm demonstrated a statistically significant and clinically relevant difference compared to placebo, though the 2-mg dose arm was not statistically significantly different compared to placebo. Dasotraline was generally well-tolerated. The most common treatment-emergent adverse events (TEAE, reported in 5 percent or more of patients and greater than placebo) included: insomnia, decreased appetite and weight decreased. The overall discontinuation rate due to TEAEs in dasotraline-treated individuals was 9.3 percent, Sunovion said.

Shares of Supernus (NASDAQ:SUPN) closed Tuesday at $23, down $1.69.