Neurocrine’s Bad Dream Continues: Indiplon Approval Requires 3 More Trials

An FDA "approvable" letter for Neurocrine Biosciences' beleaguered insomnia agent indiplon requests an additional safety study comparing the 10 mg dose to a marketed product, the firm reported Dec. 13. The firm was "very surprised" by the letter, which requests three new studies in all, Neurocrine CEO Gary Lyons stated during a same-day conference call.

"It was our full intent that we would … [get] an approvable, or an approval, or approvable pending labeling negotiation."

"We have been in discussions related to the label with the agency over the last three weeks," Lyons noted. "Directionally, there was, I guess, one could say, no evidence that we would receive anything that was short of an action going forward allowing us to market and commercialize this product."

The Dec. 12 letter indicates the drug is approvable with three conditions: the firm must conduct an additional trial comparing 10 mg indiplon to a marketed insomnia agent, a 12-week efficacy trial of the 5 mg dose in elderly patients, and a preclinical study evaluating indiplon in the third trimester of pregnancy.

The request for additional safety studies, in particular, "appears, I think, unprecedented, but we need clarification on exactly what the issues are," he stated.

Pending discussions with the agency, which Neurocrine planned to have by the end of 2007, the firm is unsure how long those trials will take. But according to Neurocrine, the elderly trial would be at least an 18-month project.

FDA's decision is a major setback for Neurocrine, which had been prepared to announce a new commercialization deal with a leading pharma company during the call.

"That agreement was signed, ready to execute, and to be announced on this day. So needless to say, our prospective partner at this point is very disappointed. We will continue our discussions with them as we seek more clarity from the agency," Lyons said.

The company was previously partnered with Pfizer, which dropped out of a development deal in mid-2006.

That came after FDA issued an "approvable" letter for indiplon 5 mg and 10 mg immediate-release capsules, in conjunction with a "not approvable" letter for the 15 mg extended-release version.

Neurocrine resubmitted the application for the 5 mg and 10 mg formulations in June for the treatment of insomnia in both adult and elderly patients. FDA, in acknowledging that resubmission, indicated it "constituted a complete response to our May 15, 2006, action letter, which means that we adequately addressed any and all of the issues," Lyons maintained.

The letter had requested "primarily re-analyses of existing studies, and there were no questions or comments related to that. So, what we can conclude is that we adequately addressed what the FDA had asked us [to] last time around."

In regard to the new safety study, Chief Medical Officer Chris O'Brien asserted that "the kinds of events that they are interested in looking at are … extremely low-frequency events that, frankly, with indiplon 10 mg capsules in adults, are exceedingly rare."

"I haven't even had time to sit down and kind of do the math on how big a study that would be. But to find a difference between a marketed product and indiplon for some of these low-frequency events would be a massive, long-term trial to have any confidence in the interpretability of the output," he added.

It is unclear what comparator would be used, but Neurocrine noted that in Phase I studies the company evaluated indiplon versus zopiclone. That drug is similar to Sepracor's Lunesta (eszopiclone).

It appears that FDA may want more information regarding class effects, Neurocrine said. Indiplon is a non-narcotic, non-benzodiazepine agent that has been shown to bind more selectively to the specific subtype of GABA-A receptors that promote sleep.

The type of low-frequency adverse events which the agency is concerned about - such as sleepwalking, binge eating or sleep driving - were seen in marketed insomnia drugs including zolpidem (Sanofi-Aventis' Ambien and generics).

The situation with indiplon IR puts other plans on the backburner for now. The company had intended to pursue additional studies in the ER formulation, as well as a sleep maintenance indication. The same day the approvable letter was announced, the firm laid off over half of its staff.

- Brooke McManus ([email protected])