Vanda gains easy panel backing for tasimelteon

Vanda Pharmaceuticals had a relatively easy time of it at the 14 November meeting of the FDA's Peripheral and Central Nervous Systems Drugs Advisory Committee (PCNSAC), which backed approval of the company's experimental drug tasimelteon as a circadian regulator to treat non-24-Hour disorder (non-24) in patients with total blindness.

Given the FDA's clinical reviewer already had recommended approval of the drug ahead of the meeting, the series of positive votes out of the PCNSAC came as little surprise (scripintelligence.com, 12 November 2013).

Although trading of Vanda's shares was halted during the trading day on 14 November, the stock soared 22% after hours.

"There is substantial evidence of effectiveness for tasimelteon in the treatment of non-24 hour disorder," said Dr Devanand Jillapalli, a clinical reviewer in the FDA's Division of Neurology Products.

The committee agreed, voting 10-0, with one abstention, substantial evidence of efficacy was presented for tasimelteon in non-24, a condition in which people have an inability to synchronize, or entrain, the so-called "master body clock" with the normal day-night cycle.

The condition affects a majority people with total blindness, with up to 100,000 Americans experiencing the disorder.

While most people's master body clock runs naturally longer than 24 hours – with light the primary environmental cue that resets it each day – the clock in patients with non-24 disorder is not reset and continually delays, resulting in prolonged periods of misalignment between their circadian rhythms and the 24-hour day-night cycle, including the timing of melatonin and cortisol secretion.

As a result of that misalignment, the sleep-wake cycle is significantly disrupted and social and occupational functioning is impaired.

There currently are no treatments approved in the US for non-24 disorder, but doctors often prescribe melatonin as an off-label therapy.

Panelist Dr Robert Sack, a professor of psychiatry at Oregon Health and Science University in Portland, lamented there is no commercial support for going through the extensive trials that would be required for melatonin to be approved by the usual FDA criteria, "and consequently, it has remained underutilized," even though it is effective.

Vanda is seeking approval of tasimelteon, which it plans to market under the brand name Hetlioz, as the first member of an established pharmacologic class of circadian regulators.

The drug, a dual melatonin receptor agonist with selective agonist activity at the MT1 and MT2 receptors, aims to reset the master body clock in the suprachiasmatic nucleus, resulting in the entrainment of the body's melatonin and cortisol rhythms to align to the 24-hour day-night cycle.

Vanda's application is based on the results of two pivotal efficacy studies, known as SET (3201) and RESET (3203).

The trials independently substantiated the clinical benefit for tasimelteon, the FDA's Dr Jillapalli told the committee.

"I thought these were lovely studies and the results were very compelling," said panelist Dr Robert Clancy, a professor of neurology and pediatrics at the University of Pennsylvania School of Medicine in Philadelphia.

But Dr Sacks said he had somewhat mixed feelings about backing the efficacy of tasimelteon.

Nonetheless, he said, "I suspect we are on the road to approving this drug to be licensed."

At the 14 November meeting, the FDA sought its panel of advisers thoughts on whether non-24 should even be considered an indication for US approval of a drug therapy.

The committee overwhelmingly said "yes" – voting 11-0, although the vote by panelist Dr Justin Zivin, professor emeritus at the University of California San Diego, actually was registered as a "no," because he had "pressed the wrong button."

Dr Zivin was the only negative vote on the FDA's question about whether the clinical endpoints Vanda used for the tasimelteon studies was appropriate to support a non-24 indication.

"I think this scale is unnecessarily complex, and the more complex it is, the more likely it is to be irreproducible," Dr Zivin said.

Vanda had proposed a primary endpoint of entrainment of the circadian melatonin rhythm as measured by the urinary metabolite of melatonin, aMT6s.

But the FDA did not accept a biomarker-based endpoint because a wealth of existing scientific knowledge about circadian rhythms suggested the clinical benefit from entrainment in non-24 would occur in a reasonably brief period of time, and would be readily measurable in terms of benefit on sleep.

So the agency asked Vanda to pick a primary endpoint capable of demonstrating a clinical benefit from tasimelteon and requested the company show that the circadian symptoms of non-24 were improved, he said.

The FDA and Vanda had agreed during development that nighttime total sleep time and daytime total nap time were reasonable measures of clinical benefit in non-24.

They also agreed that because symptoms are cyclical in non-24, an endpoint that focused on sleep on the days when symptoms were worst would have the greatest likelihood of identifying a beneficial effect of tasimelteon.

Vanda included the clinical endpoints lower quartile of nighttime total sleep time (LQ-nTST) and upper quartile of daytime total sleep duration (UQ-dTNT) as secondary endpoints.

There also was agreement between Vanda and the FDA that the clinician global impression of change (CGIC) could contribute to evidence of clinical benefit, and this too was a secondary endpoint.

Vanda also included responder analyses of those endpoints to try to demonstrate the beneficial effect of tasimelteon was as large as would be expected if the drug had a specific effect on circadian alignment, not only a soporific effect.

In addition, the company devised the midpoint of sleep timing (MoST) endpoint to illustrate the timing, not just the amount of sleep was changed by tasimelteon.

The panel of advisers said they felt comfortable with tasimelteon's safety profile – voting unanimously any issues had been adequately addressed for the non-24 hour indication.

"There appears to be very low adverse events," said panelist Dr Michelle Mielke, an associate professor of epidemiology at the Mayo Clinic in Rochester, Minnesota.

But given the small number of patients in SET and RESET, Dr Mielke insisted postmarketing follow-up studies would need to be conducted.

Dr Sacks agreed.

"The safety profile may change over time and should be monitored," he said.

Dr Sacks also called for more physician education programs to be created about non-24 to provide prescribers more understanding of the condition.

The FDA is expected to make a decision by 31 January 2014, the Prescription Drug User Fee Act action for the tasimelteon NDA (scripintelligence.com, 30 July 2013).

Sagient Research's BioMedTracker, an affiliate of Scrip, put the chances of tasimelteon gaining the FDA's blessing in non-24 at 89%, which is 8% above the average probability of US approval for the same indication based on the historical performance of medicines in the same development phase.