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By Jennifer Boggs
Assistant Managing Editor
Shares of Targacept Inc. shot up a whopping 137 percent on news that TC-5214 hit its endpoints - bypassing expectations - in a Phase IIb study in major depressive disorder, giving the firm an edge in ongoing partnering discussions.
Top-line data from the Phase IIb study showed that subjects treated with TC-5214, a nicotinic channel blocker, as an add-on therapy to selective serotonin reuptake inhibitor citalopram (Celexa) showed a statistically significant change from baseline on the Hamilton Rating Scale for Depression-17 compared to placebo. And the "p value" of 0.0001 is one "that most of us have never seen before," said Don DeBethizy, president and CEO of the Winston-Salem, N.C.-based company.
"You just don't get a drug like this very often," he told BioWorld Today, a sentiment echoed on Wall Street, as investors sent Targacept's shares (NASDAQ:TRGT) soaring $4.19 to close Wednesday at $7.25.
It's a nice boost for Targacept, which hit some clinical snags last year when AZD3480, an alpha4beta2 neuronal nicotinic receptor partnered with AstraZeneca plc, fell short in two mid-stage trials in Alzheimer's disease and schizophrenia. Investors who worried that that those failures would leave that drug dead in the water were able to breathe a sigh of relief last week when London-based AstraZeneca opted to advance AZD3480 in attention deficit hyperactivity disorder. Better yet, that move was accompanied by a $10 million milestone payment to Targacept, with the potential for up to $100 million more down the road.
Having that deal in place - and with about $80 million in the bank as of March 31 - the impressive Phase IIb data positions the firm even more advantageously to enter negotiations for TC-5214. Analyst Bret Holley, of Oppenheimer & Co. Inc., expects a competitive bidding process, estimating that a partnership "could generate a sizeable up-front payment for Targacept and significant royalties on TC-5214's potential sales," he wrote in a research note.
Thanks to a study conducted by the National Institute of Mental Health, the market for add-on therapy in major depression appears pretty substantial. The five-year study involving 3,000 patients taking citalopram - "fortunately, for us, it was same SSRI we were using in our trials," DeBethizy said - showed that about 63 percent of participants failed to achieve remission.
An estimated 14.8 million people in the U.S. are believed to suffer major depression, and "63 percent of that would be 9.3 million," he said.
Globally, major depression affects nearly 20 million people.
SSRIs such as citalopram are "good treatment options," DeBethizy said, but patients frequently have to take two or three courses of therapy. Targacept's drug is designed to stem the cholinergic system that becomes overactive in depression patients and "bring people back to normal."
Targacept's trial was conducted in two phases. After enrolling 579 subjects to first-line treatment with citalopram for eight weeks, those whose Montgomery-Asberg Depression Rating Scale score had improved less than 50 percent and was no lower than 17, were moved into the second part of the study to continue citalopram treatment in addition to either TC-5214 or placebo. The intent to treat population included 265 subjects.
Early results were clear, DeBethizy said, with TC-5214 yielding responses in as early as two weeks. After eight weeks of treatment, "basically, we had a line that never flattened," whereas the placebo group "flattened out at about eight weeks," he said.
In addition to hitting the primary endpoint, the drug also hit all secondary efficacy measures, including assessments of depression, irritability, disability, cognition, severity of illness and global improvement. The trial recorded one serious adverse event - a seizure in one patient - but it's not clear whether it was treatment-related.
Targacept plans to release detailed data at the October Society for Neuroscience meeting in Chicago for people "to really dig in to," DeBethizy said. And, in the meantime, the firm will be moving ahead with FDA talks and planning for a Phase III trial to start (with a partner) in the second half of next year. "That's pretty aggressive but doable," he said.
The company also is testing TC-5214 in resistant hypertension. In April, it started a Phase II exploratory study as an augmentation therapy in that indication. | 
