FDA Holds To High Standards For Insomnia Drugs With Second “Complete Response” For Transcept’s Intermezzo

FDA’s second “complete response” letter for Transcept Pharmaceuticals’s Intermezzo continues the strict scrutiny the agency has given recent candidates for sleep maintenance insomnia indications.

Sleep maintenance and duration claims are attractive as a relatively uncrowded segment of the insomnia field. Competition from both branded and generic agents is extensive for the traditional insomnia claims regarding difficulties in sleep onset.

But the specter of the difficulties experienced by sponsors seeking sleep maintenance insomnia claims must be keeping Transcept execs awake at night. Sanofi-Aventis walked away from its NME candidate for patients with difficulties staying asleep, Ciltyri (eplivanserin), in late 2009 after a “complete response” letter. Somaxon’s Silenor (doxepin) was approved in March 2010, but only after two CRLs questioning the drug’s efficacy (Also see "Somaxon Sleep Aid Silenor Not Effective, FDA Says" - Pink Sheet, 7 Dec, 2009.).

As a similar cluster of CRLs in the obesity area in the last two years shows, FDA is strict in its review of drugs for lifestyle indications. Strategies for de-risking NDAs, like basing candidates based on molecules already in wide use for other indications, have not appeared to help – witness Orexigen’s dispute with FDA over the CRL for Contrave (bupropion/naltrexone) for obesity, (Also see "Obesity Drugs Go Back To The Drawing Board; FDA To Hold Advisory Committee On CV Risk" - Pink Sheet, 1 Jun, 2011.).

Transcept’s Financial Jeopardy

FDA’s second “complete response” letter for Intermezzo would appear to leave Transcept Pharmaceuticals high and dry in terms of its collaboration with Purdue Pharmaceutical Products, as the company is unlikely to meet necessary deadlines associated with milestone and marketing payments.

Purdue is working with Transcept to develop and commercialize Intermezzo, a sublingual formulation of the insomnia drug zolpidem specifically intended for use when a middle-of-the-night awakening is followed by difficulty returning to sleep. FDA has already cleared the active ingredient as Sanofi-Aventis' Ambien, the market-leading insomnia agent.

Purdue would not have to meet minimum spending requirements for sales and marketing if Intermezzo is approved after July 31, and would not have to make any portion of a $30 million milestone payment if approval is gained after Sept. 23, Transcept said in a July 14 release announcing the CRL.

It is highly unlikely an approval could be gained by either date. Aside from the time it will take for Transcept to submit its response to the action letter, FDA will have another two to six months to review the resubmission – a timeframe that would likely go well beyond the Sept. 23 milestone payment date.

Transcept could chose to use FDA’s formal dispute resolution process to deal with issues in the CRL, which would require a 30-day agency response once the request is filed. The response could take longer if the agency decides it needs additional information.

The company said in the statement it planned to meet with FDA about possible next steps. It revealed that the letter asks for more studies of impairment the morning after dosing and potentially another driving study to prove the risk is acceptable.

Purdue said in a written statement it was disappointed with the CRL and was working with Transcept to evaluate the issues described in the letter. It declined to comment on whether it would re-evaluate its collaboration with Transcept.

Questions Answered, FDA Asks More

Problems with side effects led to the first "complete response" letter, announced in October 2009, but FDA raised additional concerns in the new letter, Transcept said.

FDA confirmed that Intermezzo had demonstrated efficacy, but said it could not conclude the drug could be used safely based on the NDA’s contents, according to the company statement. According to the company, the agency said during the review it became concerned patients in specific demographic groups with high zolpidem blood levels could be at risk of unacceptable next-day impairment.

The proposed Intermezzo label states the drug should only be taken when the patient has at least four hours of dedicated sleep time remaining.

Transcept presented sub-population analyses during the review cycle. Some demographic groups showed high blood levels, but the company found they did not correlate with an increase in the next-day residual effects. The company used the Digit Symbol Substitution Test, a measure of cognitive function that had been used throughout the drug development program, to measure next-day effects, but FDA is now saying DSST may not properly distinguish the possible zolpidem effects on driving ability, according to the company statement.

After receiving its first CR letter, Transcept conducted a driving impairment study to address FDA concerns about the effects on patients’ ability to drive the morning after taking the drug. Results were encouraging, finding that patients who drove four hours after taking Intermezzo did not show statistically significant next-morning effects on standard deviation of lateral position, a common surrogate measure of driving performance (Also see "Transcept's NDA Intermission For Insomnia Drug Intermezzo Set To End In First Quarter" - Pink Sheet, 19 Oct, 2010.).

Study Of Weight, Demographic Effects Suggested

FDA is accepting that a new single-use dose pouch adequately addressed its concerns about inadvertent re-dosing in a single night, another issue in the first letter.

Transcept redesigned the package and wrote new patient instructions. Patients are told to take one pouch to their bedside and leave the rest in their medicine cabinet. If they took a dose of Intermezzo, patients were told to leave the empty pouch at their bedside so they did not forget they took it.

However, FDA said in the new CRL it is still concerned some patients will take the drug with less than four hours of bed time remaining and said a study testing driving performance three to 3.5 hours after dosing should be part of Intermezzo’s safety review.

The agency said a dosing error study would not be required.

The company said it already had studied driving performance beginning three hours after dosing and found statistically significant effects in the primary analysis. A secondary analysis found mean effects on driving ability three hours after dosing were statistically different from placebo, but below the threshold of potential driving impairment described in the literature. FDA said in the CRL those results indicated clinically meaningful impairment.

The agency suggested Transcept demonstrate next-morning blood levels do not lead to unacceptable next-day impairment risks after mitigation strategies are implemented. The agency also said the company should study whether body weight and demographics contribute to higher blood levels the morning after dosing and develop strategies to decrease them.

Those requests suggest the company will have to develop a risk mitigation strategy before approval, which, added to the other requests, means a not inconsiderable amount of work left for FDA to reconsider the drug.

– Derrick Gingery ( [email protected] )