FDA Panel Gives Nod to Circadian Rhythm Disorder Drug

Pauline Anderson

November 20, 2013

Blind patients with a rare circadian rhythm condition called non–24-hour sleep-wake disorder, or non–24-hour, that affects their sleep and quality of life may soon rest a little easier.

After a day-long meeting, the US Food and Drug Administration's (FDA's) Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) almost unanimously agreed that tasimelteon (Vanda Pharmaceuticals Inc), a melatonin agonist, has been proven to be effective and safe for patients with non–24-hour.

Blind people don't have input from the eyes about environmental light levels that sighted individuals have. Light information fails to reach the suprachiasmatic nuclei in the hypothalamus to synchronize their internal clock.

As a result, levels of the hormone melatonin, which is produced by the pineal gland and plays a key role as a feedback regulator of the master circadian clock, peak at later and later times each day and the sleep-wake cycle becomes progressively out of sync with the normal 24-hour cycle.

Some blind people develop non–24-hour, a chronic and debilitating disorder that can have a serious impact on sleep patterns and daily social and occupational functioning.

There's currently no available treatment for non–24-hour. Vanda Pharmaceuticals Inc has submitted a new drug application for its tasimelteon capsules.

Resetting the Circadian Clock

Tasimelteon (proposed tradename, Hetlioz), is designed to reset the circadian clock daily. Vanda carried out 2 pivotal phase 3 multicenter randomized, placebo-controlled efficacy studies of 20 mg of tasimelteon in patients with non–24-hour. The first — Safety and Efficacy of Tasimelteon (SET) — was a 26-week study that included 84 patients. The second study — Randomized Withdrawal study of the Safety and Efficacy of Tasimelteon (RESET) — lasted 19 weeks and included 20 patients, all of whom had been previously screened in SET and were "entrained" during the open-label tasimelteon treatment.

"Entrainment" of the circadian rhythm, as measured by urinary 6-hydroxymelatonin sulfate (aMT6s), a main metabolite of melatonin, was the primary efficacy endpoint for SET. Scores on the 24-hour Clinical Response Scale (N24CRS) was another defined endpoint for SET. Outcomes for RESET included maintenance of entrainment (aMT6s) and maintenance of clinical response.

According to results presented at the meeting by Vanda representatives, the research demonstrated that tasimelteon entrains the master clock (both melatonin and cortisol) and has clinically meaningful effects on the sleep-wake cycle in terms of the timing and amount of sleep, and improved measure of global functioning.

For example, according to Louis Licamele, PhD, senior director, clinical, Vanda Pharmaceuticals Inc, SET showed a statistically significant between-group difference on the primary endpoints of entrainment (2.6% in the placebo group vs 20.0% in the tasimelteon group) and of clinical response (entrainment plus N24CRS score of 3 or greater): 0.0% for placebo and 23.7% for tasimelteon.

Each component of the N24CRS also improved, including increased nighttime sleep, increased daytime sleep, and global functioning.

More than half of the patients in SET responded to the drug. Tasimelteon succeeded in entraining the "master" clock in 59% of patients by month 7.

In RESET, the percentage of patients with maintenance of entrainment was significantly higher in the treatment group (90%) than in the placebo group (20.0%) About 90% of people in the RESET trial became unentrained once they were taken off the drug. The response rate for RESET was also about 50%.

As for safety, the company provided data demonstrating that the drug is generally safe and well tolerated, with no related serious adverse events. It's not associated with symptoms of residual, next-day effects or somnolence and is not associated with increased risk for suicidality on withdrawal or with any endocrine safety signal.

FDA Presentation

The FDA reviewers disagreed on the primary endpoint for the drug trials. According to the Devanand Jillapalli, MD, clinical reviewer, Center for Drug Evaluation and Research (CDER) of the FDA, the primary efficacy evaluation for tasimelteon should have been based on clinically meaningful primary endpoints "that directly assess prolonged life and improved physical condition" and not on a "surrogate" such as a melatonin-based biomarker "that does not directly assess clinical benefit."

According to Vanda representatives, however, entrainment is not a surrogate but is definitional of the disease.

"We felt that it was a reasonable compromise to do 2 things: to have entrainment as a primary endpoint in a causal pathway but also to attempt to develop a scale, the N24CRS, and allow this to be a clinical endpoint to capture the variability of the disorder," said Mihael H. Polymeropoulos, MD, chief executive officer of Vanda. "Regardless of whether entrainment is used or not, the non24CRS is positive."

The FDA also took issue with analytical methods. Jingyu Luan, PhD, statistical reviewer at CDER, said both studies used analysis of covariance with study site as a factor, whereas permutation analysis of covariance without site consideration would have been more appropriate for analyzing the clinical endpoints.

In addition, FDA reviewers felt that the 12 patients who were excluded from the intention-to-treat analysis of the SET study because of lack of data should have been included. However, as Dr. Polymeropoulos explained, non–24-hour is a cyclical disorder for which data have to be collected over a relatively long period to capture the entire repeated sleep-wake pattern and "to have enough confidence and enough density of data."

At the end of the day, though, the FDA analysis concluded that tasimelteon may be beneficial for non–24-hour on the basis of all the clinical endpoints except for nighttime sleep time, and that substantial evidence of its effectiveness has been shown. Its overall conclusion was that the benefits of tasimelteon outweigh its risks in patients with non–24-hour, said Dr. Jillapalli.

During debate, panel members generally agreed that a drug such as tasimelteon would fill a void, but some expressed concerns about lack of clinical measures or the complex nature of variables included in the research. One panel member pointed out that although the studies may have shown that the drug decreases daytime sleep, they didn't appear to show the quality of the increased daytime wakefulness — in essence, how tired patients were even though they weren't napping.

Another issue raised by a panel member was that melatonin is already available and is also effective. "I can't in good conscience feel great about introducing a drug that's foreign to the body which a person might be taking for a lifetime when there's another agent available that probably would do the same thing."

Appropriate Indication

The panel voted 10 to 1 — it would have been unanimous but 1 member mistakenly voted against the motion — that non–24-hour is an appropriate indication for FDA approval of this drug.

"The sponsor gave a very nice story linking the neuroanatomy, the neurophysiology, the expected consequences, what the data actually shows, and how this is mitigated by their interventions so altogether; I thought it was a well told story that's plausible and believable," said Robert R. Clancy, MD, professor, neurology and pediatrics, University of Pennsylvania School of Medicine, Philadelphia.

"It's fairly clear that this disorder is very burdensome to patients that have it and that anything that can be done to treat it and to help them should be done," said Michelle M. Mielke, PhD, associate professor, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota.

For Robert L. Sack, MD, professor, psychiatry, Oregon Health and Sciences University, Portland, the presented research "drew upon the FDA regulatory experience with hypnotic medications," and he felt that a different sleep measure might be more appropriate for future studies.

"Maybe there needs to be serious consideration of a different category of pharmacology, one that incudes circadian phase shifting drugs, and of what sort of outcome measures will be appropriate for that," said Dr. Sack.

Charmane Eastman, PhD, professor, Behavioral Sciences Department, Biological Rhythms Research Lab, Rush University Medical Center, Chicago, Illinois, pointed out that "entrainment is more than a measure of sleep" and that eating "at the wrong phase" and other functions can affect patients with non–24-hour.

The panel strongly agreed (in a vote of 10 to 1) that the clinical endpoints used in the drug development program are appropriate.

The only member who disagreed was Justin A. Zivin, MD, professor emeritus, University of California at San Diego. He thought the endpoints were "unnecessarily complex."

Dr. Clancy voted "yes" because, he said, "if I was a patient and confronted with these issues, the 2 things I would want is more sleep at night and less during day and that's what these variables capture so it sounded reasonable to me."

Panel chair, Nathan B. Fountain, professor, Department of Neurology, University of Virginia School of Medicine, Charlottesville, agreed the endpoints were appropriate but said he would have liked to have seen some clinical measure and less complexity.

As for efficacy, all but 1 member voted that substantial evidence of efficacy has been demonstrated. Dr. Zivin chose to abstain because he couldn't decide whether the drug is effective or not, partly because it "failed on its primary endpoint."

The group unanimously voted that the safety of tasimelteon has been addressed. However, as 1 delegate pointed out, given the response rate of 50%, clinicians may be tempted to increase the dose, so the safety profile may change with time and should be monitored.


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