Another Miss for Targacept; TC-5619 Fails in ADHD Trial

By Jennifer Boggs
Managing Editor

Targacept Inc.'s TC-5619 missed its endpoint in a Phase II study in inattentive-predominant attention deficit hyperactivity disorder (iADHD), the latest in a string of disappointing news for its neuronal nicotinic receptor (NNR) pipeline.

The iADHD study randomized 175 patients to receive one of two doses of TC-5619 (5 mg or 25 mg) or placebo once daily for four weeks. The primary outcome measure was defined as the Inattention subscale of the Conners' Adult ADHD Rating Scale-Investigator-Rated and was designed to confirm a signal seen in that patient subpopulation in an earlier Phase II trial, said Alan Musso, senior vice president of finance and administration and chief financial officer.

Though the alpha 7 NNR drug missed its endpoint in that earlier study in ADHD, further analysis indicated potential in the inattentive-predominant patient group. Targacept designed the latest Phase II study hoping to confirm those results in iADHD, but final data showed no clear improvement with TC-5619 over placebo, though the drug was found to be safe and well tolerated.

"We're disappointed with the outcome, but we're still excited about our other ongoing programs," Musso told BioWorld Today.

One of those programs involves TC-5619 as a potential treatment for negative symptoms and cognitive dysfunction in schizophrenia. A 450-patient Phase II trial is relying on the Scale for the Assessment of Negative Symptoms as the primary outcome measure, and data are expected in mid-2013.

The good news is that the schizophrenia indication is likely the bigger opportunity for Targacept, with Deutsche Bank analyst Robyn Karnauskas modeling a $1.35 billion peak potential. And the failure in iADHD should not carry over into the schizophrenia trial, Karnauskas added, assigning a "30 percent probability to success."

Pending positive results from that study, Targacept could be positioned to seek out another partner for the drug, which could also have implications in Alzheimer's disease. London-based AstraZeneca plc passed on an option to TC-5619 in 2001. (See BioWorld Today, May 23, 2011.)

Elsewhere in its pipeline, Targacept continues to develop AstraZeneca-partnered AZD3480, a small molecule designed to act on the alpha4beta2 NNR subtype. That drug is in a Phase IIb trial in mild to moderate Alzheimer's disease.

Targacept also hasn't given up on TC-5214, the drug that fizzled in Phase III studies as an adjunct treatment for major depressive disorder (MDD) last year, prompting AstraZeneca to bail on that potential $1 billion collaboration. (See BioWorld Today, Dec. 4, 2009, and Nov. 9, 2011.)

Further preclinical and clinical analyses, along with the drug's mechanism of action, indicated the possibility of developing TC-5214 in overactive bladder. Targacept reported physiological findings for the drug believed to be consistent with marketed treatments for overactive bladder. Prior studies also showed that more than 90 percent of TC-5214 is eliminated unchanged through the bladder, supporting use of a low dose and creating the potential to minimize unwanted side effects.

A Phase IIb study is set to start in the first half of 2013. And in overactive bladder, "Phase II success pretty consistently translates into Phase III," Musso noted. "There's a more objective endpoint," than the one used in the MDD study.

Winston-Salem, N.C.-based Targacept will be focusing its resources on those three programs. The firm, which cut 46 percent of its staff in April, anticipates another round of layoffs, though it hasn't yet disclosed specifics. The company also continues the search for a new CEO to replace J. Donald deBethizy, who stepped down in June.

Targacept has suffered some hard knocks in the past year, with its stock hammered on the failed MDD trial and the loss of the AstraZeneca deal for TC-5214, followed by mid-stage failures of TC-6987, an alpha 7 NNR, in asthma and diabetes.

The company's shares (NASDAQ:TRGT) fell 54 cents, or 11 percent, to close Monday at $4.31.

But Targacept remains well-capitalized going forward. As of June 30, the firm had about $205.9 million in cash.