Rarely has a 7-year old with a rash caused the stock price of a major corporation to gyrate so dramatically.

On March 23, 2006, the FDA rejected Cephalon’s application for Sparlon, a renamed Provigil that is effective for treating ADHD. Immediately, the company’s stock lost about 10% of its value, or about $18 million overall; later in the day, it rebounded.

The debate centered on a single subject in one of the three clinical trials submitted in Cephalon’s FDA application. In trial #311, a 7-year old who had been randomized to Sparlon developed a serious rash and fever that might have been the dreaded and potentially fatal Stevens Johnson Syndrome (SJS). The child recovered, and Cephalon argued that he might have had a viral rash instead of SJS. Nobody could agree, and the only dermatologist on the FDA advisory committee felt that SJS “couldn’t be ruled out.” (see www.thepinksheet.com, posted March 23, 2006). For this reason, the committee deferred immediate approval, and requested that Cephalon do another study, this time of 3,000 children, to make sure that Sparlon doesn’t cause SJS.

Not that SJS was the only concern raised by the FDA. There were a number of psychiatric adverse effects in young kids taking Sparlon, including suicidal ideation, psychosis, and agitation. Finally, rates of insomnia (27%) and severe appetite loss (16%) were both higher than the FDA would have liked.

Efficacy was not the issue here. The committee unanimously voted that the efficacy data was good. The problem is that in order to achieve a good response in kids with ADHD, the dose has to be pushed up into the 400 mg range, leading to the high reported rate of side effects.

So, did Cephalon agree to do that safety trial on 3,000 kids? No. Instead, Cephalon tried to get their approval without all that extra work. The company marshaled a team of dermatological experts to review the records of the 7-year old and submitted a packet of “new information” to the FDA. This was not a shot in the dark: the FDA took this seriously enough to officially extend its review period for Sparlon in order to look over this evidence.

But it was all for naught. On August 9, 2006, just as we were going to press with this article, Cephalon announced that the FDA had rejected their dermatological evidence, and had sent them a second non-approvable letter. Rather than proceed with the requested safety trial, Cephalon has decided to completely drop development of Sparlon.

This is no huge tragedy for our patients, however, since “Sparlon” is nothing other than Provigil, with the modafinil molecules packed into a different looking pill and with a bizarre array of dosing options (75 mg, 170 mg, 255 mg, 340 mg, and 425 mg). Provigil comes in a breakable 200 mg strength, allowing similar dosing flexibility. So why did Cephalon even bother to attempt this new version? Because Provigil is about to go generic, and FDA rules allow companies to win new patents for expiring drugs if they can furnish evidence for a new indication.

With their Sparlon strategy moribund, Cephalon is moving on to its second attempt to protect itself from Provigil’s impending loss of patent protection. They have recently introduced “Nuvigil” (armodafinil), the purified R-isomer extracted from racemic Provigil. Nuvigil just got the approvable letter from the FDA for all the same indications that Provigil currently has: sleepiness caused by narcolepsy, shift work disorder, and sleep apnea. Does it have any therapeutic advantages over Provigil? That’s still unclear, but it may last a bit longer, as demonstrated in one study of healthy male volunteers (Curr. Med. Res. Opin. 2006;22(1):158-167); whether that’s an advantage or disadvantage will depend on the particular patient. Regardless, you can be certain that Cephalon reps will soon be encouraging you to switch all your sleepy patients from Provigil to Nuvigil; we suggest you ask them to show you the hard data demonstrating any advantages before making the switch.

Meanwhile, Cephalon was recently written up as a model pharmaceutical company in BusinessWeek magazine (April 24, 2006). The magazine commended the firm for working on “several drugs at once” in order to buffer itself from the effects of generic competition. Unfortunately, the periodical didn’t get their facts quite right; they’re actually working on the same drug at once!

TCPR Verdict:
Sparlon bites the dust; prescribe modafinil instead!