Tarnished HALO For Targacept/AstraZeneca Nicotinic Receptor Modulator

Targacept and AstraZeneca halted further development of their neuronal nicotinic receptor modulator AZD3480 for cognitive dysfunction in schizophrenia after the drug failed to meet its primary endpoint in the Phase II HALO trial, but a final decision on the compound will wait for an ongoing trial in attention-deficit/hyperactivity disorder.

The failed trial "rules '3480 out for CDS," Targacept CEO Donald deBethizy said during an after-the-bell Dec. 8 conference call to announce the top-line results. The companies, which signed a deal in 2005 to partner on Targacept's NNR platform, are awaiting data from a Phase II trial in ADHD to determine the future of the compound.

This is the second failed trial for '3480. In September, Targacept and AstraZeneca announced the drug did not meet its primary endpoint in a Phase II Alzheimer's disease study, adding pressure on the schizophrenia trial to be successful (¹ Pharmaceutical Approvals Monthly September 2008, p. 26).

AZD3480 still has one lap left in the race - the ADHD study, with data expected in the first half of 2009. Those data, along with encouraging results from secondary endpoints in the AD trial and several ongoing evaluations in undisclosed indications, will determine whether AstraZeneca pursues later-stage development of the drug.

In the trial in cognitive dysfunction in schizophrenia, the NNR agonist failed to meet the primary endpoint, improvement in the five domains of the computerized battery test IntegNeuro to assess cognitive function.

The randomized, double-blind, placebo-controlled, dose-finding study evaluated three doses of '3480 versus placebo in 445 active smokers taking atypical antipsychotics. The 12-week study enrolled smokers because 70 percent to 90 percent of schizophrenics use tobacco as self-medication, deBethizy explained.

"The bad news was that it didn't work," he said, finding good news in the definitiveness of the answer: "no trends and no effect."

Although the companies are not pursuing '3480, an a 4?2 NNR agonist, in cognitive dysfunction in schizophrenia, deBethizy said he wasn't sure whether the data rule out all a 4?2 compounds in the space. "But clearly our follow-on compounds that are in development [for schizophrenia] still are a 7 compounds," he added.

Targacept's pipeline does include other early-stage a 4 agents, including the preclinical a 4?2 agonist TC-6683, with plans to move into Phase I by year-end, and the Phase I CDS therapy TC-5619, an a 7 agonist. The Phase II a 4?2 compound TC-5214 for major depressive disorder is enrolling ahead of schedule, deBethizy said, and is one of the firm's "lower-hanging fruits." Data are expected in mid-2009.

AZD3480 is not the first disappointment in the NNR field. Several other companies have discontinued development of their a 4?2 compounds after poor showings. Sanofi-Aventis killed the Phase IIb smoking-cessation drug SSR-591813, and GSK halted studies of GW-280430 and licensed the drug to Avera Pharmaceuticals.

Setbacks in the NNR space aren't new to AstraZeneca or Targacept either. Both had failures with earlier NNR compounds - AstraZeneca dropped its preclinical alpha-7 NNR agonist AZD0328 for Alzheimer's disease, and Targacept/GlaxoSmithKline discontinued their Phase II a 4?2 compound TC-2696 for acute post-operative pain.

That's not to say that the field is drying up entirely, or not worthwhile. Pfizer gained approval for an a 4?2 receptor agonist in 2006 - Chantix for smoking cessation - and apparently is working on a follow-up to the varenicline product. The a 4?2 receptor agonist, CP-526,555, is listed in Phase II for smoking cessation in schizophrenic patients in the clinicaltrials.gov database, but the compound is not listed on Pfizer's most recent pipeline.

Abbott is developing two a 4?2 agonists with NeuroSearch. ABT-894 is undergoing evaluation in neuropathic pain and ADHD; positive ADHD results were reported in June. Abbott also is pursuing ABT-089 for ADHD. The firms also have a Phase I a 7 receptor agonist, ABT-107, in a number of CNS diseases, including Alzheimer's and schizophrenia.

Roche recently acquired Memory and its a 7 agonist program, including the Phase IIa drug R3487/MEM 3454 currently in trials for Alzheimer's disease and cognitive impairment associated with schizophrenia, as well as the Phase Ia Alzheimer's medicine R4996/MEM 63908 (² (Also see "Roche Snaps Up Memory, Gains CNS Drugs" - Pink Sheet, 26 Nov, 2008.)).

- Becky Jungbauer ([email protected])