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By Larry Smith

Transcept (TSPT) believes that the results of the highway driving study of Intermezzo reasonably answer the concerns of the FDA that caused the agency to issue a Complete Response Letter to the NDA in October of 2009. It plans to re-submit the NDA in the first quarter of 2011.

There is reasonable hope that the FDA will agree with Transcept that the study does answer their concerns and will set the stage for approval. However, as with almost all clinical studies, there are ambiguities that might lead the FDA to conclude that the study did not answer its concerns. Transcept has a lot at stake as this would be its first commercial drug. It has been licensed to Purdue Pharmaceuticals for commercialization.

Analysts believe that if approved, Intermezzo could have good sales potential. Jason Napodano of Zachs Research has published estimates that 35% of 225 adult Americans experience nocturnal awakenings and that 11% seek prescription medicine help in returning to sleep. If just 10% of these people were to use 3 Intermezzo pills per week at a price of $5 per pill, the potential sales of Intermezzo could exceed $500 million.

Transcept is developing Intermezzo, the first insomnia drug specifically developed for middle of the night awakening (MOTN); Intermezzo is a low dose formulation of zolpidem (the active ingredient in Ambien and Ambien CR, the most widely prescribed insomnia agents). Neither Ambien, Ambien CR nor any other approved drugs for insomnia have this specific indication. This is because their effects generally last for about 8 to 10 hours.

If a patient wakes up in the middle of the night, say 3 to 4 hours before they normally wake up, and takes one of the currently available insomnia drugs, their physical performance could be seriously impaired upon awakening the next day.

On October 26, 2009, the FDA issued a Complete Response Letter to Intermezzo’s NDA, which caused the stock price to be cut in half. The FDA stated that Transcept had shown substantial evidence of efficacy for the use of Intermezzo used as needed to treat MOTN.

It also indicated that Intermezzo had not been shown to cause significant next day residual effects. However, the FDA requested an additional study(ies) to show that Intermezzo when taken as directed would not present an unacceptable risk of residual effects, with a particular emphasis on next day driving ability. The FDA also stated that the indication sought for Intermezzo was unique so that safe dosing schedule has not been established. The agency was also concerned with dosing errors that could lead to inadvertent dosing with less than four hours of bedtime remaining and inadvertent re-dosing in a single night.

Transcept began a unique study in July of 2010 to address some of the issues that concern the FDA and Monday night it released the results of this highway driving study that was designed to show that when used under the conditions recommended in its proposed labeling, Intermezzo does not adversely affect a subject’s capacity to operate a motor vehicle 4 or more hours following a middle of the night dose.

The primary measure of driving performance employed in this highway safety study was a measure called the standard deviation of lateral position, or SDLP. This measure of driving impairment was devised over 30 years ago and measures variability in lane position while driving. It has been widely used as an experimental assessment of driving performance for subjects who have taken alcohol and other mind altering drugs. However, it has never been relied upon by the FDA to evaluate the capacity of a drug to impair performance.

In designing its highway safety trial, Transcept chose SDLP as the primary point and used a new statistical analysis for evaluating SLDP which it refers to as a “symmetry analysis”. The FDA informed Transcept that this statistical methodology was a reasonable approach to measure potential next morning driving impairment. However, the FDA does not enter into contracts so that this does not necessarily mean that the FDA will ultimately accept this endpoint or the statistical analysis of the endpoint.

Glenn Oclassen, CEO of Transcept, summarized the results of this study as follows:

  • When Intermezzo was given 4 hours before driving, the symmetry analysis found no statistically significant drug effects at the pre-specified thresholds. This was the primary endpoint of the trial so that Intermezzo was successful in reaching the primary endpoint.
  • A secondary technique of statistical analysis that compares group mean effects did detect small but statistically significant differences between Intermezzo taken 4 hours prior to driving and placebo. By this statistical measure, Intermezzo narrowly missed the primary endpoint.
  • Additionally, statistically significant differences between placebo and Intermezzo were shown at 3 hours in both the primary analysis of symmetry and the secondary analysis of means. Here again, the absolute values of the mean differences between active and placebo dosed at 3 hours before driving were relatively small, Intermezzo missed on this secondary endpoint using either statistical analysis.

The key question is whether FDA will accept these results as answering the questions raised in the Complete Response Letter. Because there are no clinical precedents, it is difficult to estimate how the FDA will respond to the results of this study. Intermezzo was successful in achieving the primary endpoint using its statistical analysis plan; there was no difference between Intermezzo and placebo. However, the FDA could at its own discretion decide that this was not the right endpoint. Also, the second statistical analysis of the primary endpoint did show that there was modest impairment of driving. Additionally, based on the secondary endpoint of giving Intermezzo three hours before awakening, there was modest impairment.

The FDA’s reaction to data can be very difficult to predict and this is even more the case in a situation like this when Transcept is plowing new clinical ground with Intermezzo. There could be a positive scenario in which the FDA agrees with Transcept’s statistical analysis and the selection of the primary endpoint and concludes that the primary endpoint of the driving study was reached. In doing so, it would also have to make the judgment that the statistical failure using the different statistical analysis and reaching the secondary endpoint of three hours were not clinically significant.

It could also make the judgment that Intermezzo is a much safer alternative to other insomnia drugs that are already widely used off-label for MOTN. Conversely, it could come to the opposite conclusion on each of these points. Ultimately it is a value judgment.

Transcept was not able to design a study that could address the FDA’s also concerned with dosing errors that could lead to inadvertent dosing with less than four hours of bedtime remaining and inadvertent re-dosing in a single night. It addressed these questions with dosing measures and patient education. The FDA may or may not agree with this position.

Disclosure: no positions

Source: FDA Reaction to Transcept Insomnia Drug Trial Data Can Go Either Way