Sleep Disorder Treatment for Blind Persons May Be Marketed More Widely

Have you ever heard of “non-24”? It’s a sleep disorder that primarily affects people who are totally blind.

If you haven’t heard about it, you may start to — but unless you are blind, you should be wary. The company selling a new drug recently approved by the Food and Drug Administration (FDA) for treating this disorder no doubt would like to expand its market and may very well try to convince nonblind persons that they could benefit from it, too.

Non-24

Non-24 is a disruption in a person’s normal circadian rhythm — the 24-hour sleep-wake cycle that occurs naturally in most people and allows them to be awake during the daytime and asleep at night. The ability of the eyes to sense light during the day plays a key role in setting the body’s internal circadian clock.

Many individuals who are totally blind do not have the same 24-hour circadian rhythm as those with vision, because their eyes do not perceive light. As a result, their circadian rhythms are usually slightly longer than 24 hours, resulting in intermittent periods when they are awake at night and asleep during the daytime.[1]

An orphan drug

The new — and only — drug specifically indicated for treating non-24 is called tasimelteon (HETLIOZ), manufactured by Vanda Pharmaceuticals Inc. The FDA approved the drug on Oct. 2, 2014.

When Vanda Pharmaceuticals began developing tasimelteon, the company requested that the FDA designate the drug as an “orphan drug,” a product purportedly to treat a rare disease. The FDA may grant orphan status to a drug if it is intended for treating a disease affecting fewer than 200,000 people in the U.S. or for a disease affecting more than 200,000 people but the development and marketing of the drug in the U.S. is not expected to be profitable.[2] Companies manufacturing these drugs receive tax incentives and increased intellectual property protection, as well as financial assistance for clinical trials in some cases.[3] The FDA granted Vanda Pharmaceuticals’ request, giving the drug orphan status.

When applying for FDA approval of tasimelteon, Vanda Pharmaceuticals proposed that the drug’s indication would be only for treatment of non-24 disorder in blind patients, consistent with the product’s orphan-drug designation. During clinical trials, the drug was tested for efficacy for six months in only 52 totally blind individuals.[4] However, despite the FDA reviews and memos[5],[6] stating the proposed indication for the drug was “[n]on-24 hour sleep-wake disorder (Non-24) in totally blind patients,” Vanda Pharmaceuticals apparently was not satisfied with selling tasimelteon to only totally blind patients. Based on the inappropriate FDA-approved drug label, which does not discuss blindness in the indication, and the wording used to describe non-24 on several websites, it seems very likely that Vanda Pharmaceuticals will try to widen the definition of the disorder so that the drug is prescribed to nonblind patients as well.[7]

Widening the field

Although the clinical trials of tas-imelteon used to support FDA approval were limited to totally blind people, the wording of the FDA-approved drug label can be interpreted to mean that the drug is intended for anyone claiming to have non-24, regardless of their vision status. The label states only that tasimelteon is “for the treatment of non-24 Hour Sleep-Wake Disorder (Non-24).” The word “blind” is mentioned only once in the drug label — toward the end, in a section describing the subjects who had enrolled in the clinical trials.[8]

On the Vanda Pharmaceuticals website, the introductory page for tasimelteon — titled “Welcome to Hetlioz” — states that tasimelteon is “the first and only FDA-approved treatment for Non-24-Hour Sleep-Wake Disorder (Non-24).” The website’s home page describes non-24 as a “serious, chronic disorder” but never mentions that the drug’s approval was based on trials that enrolled only patients with total blindness.[9]

Other websites, including those of the National Sleep Foundation (NSF)[10] and the National Organization for Rare Disorders,[11] also describe non-24 as a more general affliction and not confined to patients with total blindness. Both sites claim that non-24 occurs as well in a small or unknown number of sighted people. Of note, the NSF identifies the maker of tasimelteon as one of its corporate sponsors.[12]

The statements related to non-24 sleep disorder occurring in sighted people, combined with a drug label that does not limit the approved indication to totally blind people, open the door to much more widespread use of tasimelteon than was originally understood by the FDA scientists who reviewed the trials with totally blind patients. If more widespread use were to occur, a drug tested for effectiveness for only six months in just 52 totally blind individuals could potentially be used by hundreds or thousands of sighted individuals, a population in which it was not appropriately tested. And the benefits and risks of tasimelteon could be quite different in sighted individuals than in those who are blind.

Side effects

The drug company may have had in mind eventually expanding the patient population in the future to include sighted subjects. Both Vanda Pharmaceuticals and the prior owner of the drug, Bristol-Meyers Squibb, have previously carried out efficacy studies in nonblind individuals with insomnia, no doubt in hopes of marketing the drug for this much broader indication. Vanda did not report in its new drug application for tasimelteon whether the drug was effective in treating insomnia in people who are not blind. However, one of these insomnia studies did show that elderly women with insomnia had a significantly higher incidence of daytime sleepiness compared with those taking a placebo.[13] Being elderly and sleepy during the daytime could put them at risk for falling or other accidents.

In the clinical trials for tasimelteon, the drug was more likely to be associated with several common adverse reactions compared with a placebo (see table, below).

Adverse Reactions in Totally Blind People During Clinical Trials Testing Tasimelteon[14]

Listed are adverse reactions at least twice as high in patients taking tasimelteon as in those taking a placebo. These reactions occurred in patients taking a dose of 20 mg for six months.

Because of its ability to increase daytime sleepiness, tasimelteon can cause impairment during activities requiring complete mental alertness, such as driving and the operation of heavy machinery.[15]

What You Can Do

The drug industry is intent on selling you sleep medications, and the maker of tasimelteon is likely to be no exception. If you are not totally blind and a health care provider recommends taking tasimelteon for insomnia, ask for advice on nondrug alternatives.

Public Citizen’s Health Research Group continues to advise against using prescription medications to treat sleep disorders.

WorstPills.org contains more comprehensive information on how to manage insomnia without using sleeping pills.[16]

References

[1] Non-24 Disorder Resource. Your master body clock and circadian rhythms. https://www.non-24.com/circadian-rhythms.php. Accessed November 13, 2014.

[2] Food and Drug Administration. Developing products for rare diseases & conditions. https://www.fda.gov/forindustry/DevelopingProductsforrareDiseasesConditions/default.htm. Accessed November 3, 2014.

[3] Orphan Drug Development. The science of hope: The need, the challenges and three proven strategies for successful orphan drug development. https://premier-research.com/images/uploads/The_Science_of_Hope_the_need,_the_challanges_and_three_proven_strategies_for_successful_orphan_drug_development.pdf. Accessed November 13, 2014.

[4] FDA medical reviw. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205677Orig1s000MedR.pdf (pp.147&148). Accessed November 24, 2014.

[5] FDA Summary Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205677Orig1s000SumR.pdf. (p.3) Accessed November 24, 2014.

[6] FDA Medical Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205677Orig1s000MedR.pdf. (p.2) Accessed November 24, 2014.

[7] Non-24 website. https://www.non-24.com /.

[8] Hetlioz drug label. https://www.hetlioz.com. Accessed October 21, 2014.

[9] Vanda Pharmaceuticals. Welcome to Hetlioz. https://www.hetlioz.com. Accessed October 28, 2014.

[10] National Sleep Foundation. Sighted vs. Blind. https://sleepfoundation.org/non-24/content/sighted-vs-blind. Accessed November 13, 2014.

[11] National Organization for Rare Disorders. Non-24-hour sleep-wake disorder. https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1275/viewAbstract. Accessed October 30, 2014.

[12] National Sleep Foundation. Sleep Health and Safety Sponsors and Exhibitors. https://sleepfoundation.org/%5Bmenu-raw%5D/sleep-health-and-safety-sponsors-and-exhibitors. Accessed November 13, 2014.

[13] FDA Medical Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205677Orig1s000MedR.pdf. Accessed October 30, 2014. (p.11)

[14] Hetlioz drug label. https://www.hetlioz.com/pdf/HetliozPI.pdf/. Accessed October 28, 2014. (p.3)

[15] Ibid. (p.11)

[16] Alternatives for Sleeping Problems. Worst Pills, Best Pills News. July 2010. /newsletters/view/701. Accessed November 3, 2014.