Tasimelteon

Tasimelteon

Tasimelteon is the first FDA-approved treatment for Non-24-Hour Sleep-Wake Disorder in completely blind people (12). Under the trade name Hetlioz®, it is among the class of dual melatonin receptor agonists (DMRAs) alongside ramelteon and other synthetic compounds. This new molecular entity was developed and marketed by Vanda Pharmaceuticals (3), who, to current knowledge, have not disclosed specific information regarding its discovery. Tasimelteon targets melatonin receptors MT₁ and MT₂, which are located in the brain and thought to be involved in the regulation of circadian rhythms (4). As an agonist, it binds to these receptors and acts as a regulator of sleep patterns; more specifically, it realigns the circadian rhythms in those who experience total blindness.

Tasimelteon first began trials in 2004 as a treatment for circadian rhythm sleep disorders and underwent phase III trials for insomnia in 2005 and 2007. It was granted orphan drug status for treatment of Non-24 in 2010 (9). It was first submitted in a New Drug Application to the FDA for treatment of Non-24 in early 2013, and it was recommended for approval in November of that year. The NME was then approved on January 31, 2014 under New Drug Application (NDA) 205677 and trade name Hetlioz® (1). There are currently 8 US patents protecting Hetlioz®, all owned by Vanda (2); in fact, the company recently announced the listing of a new patent in the FDA “Orange Book.” This patent was issued on September 11, 2018 and will expire in 2035 (5).

The discovery and development of MRAs has been driven by the desire to improve the efficacy of treatments for sleep-related disorders by improving aspects of melatonin, such as pharmacokinetics and half-life (7). Closely resembling the structural design of melatonin, tasimelteon was synthesized with the specific purpose of obtaining more effective treatment for insomnia (10). However, throughout testing it was learned to have a more impactful effect on circadian rhythm regulation than, for example, ramelteon, a more efficient treatment for insomnia than melatonin.

Because tasimelteon and ramelteon are DMRAs, both behave almost identically, but each has its own specialized uses, advantages and drawbacks. Tasimelteon has fourfold greater affinity for MT₂, which is believed to be more critical in “phase-shifting the clock” (14); ramelteon has ten times the affinity for MT₁ than MT₂ (12). Though tasimelteon has an overall affinity that is lesser than that of ramelteon, its half-life is subject to less variability: 1.3 ± 0.4 hours versus ramelteon’s 1 – 2.6 hours (4, 8). This ensures a lower chance of toxicity and a higher chance of proper efficacy across a broader spectrum of patients. Additionally, tasimelteon is less affected by first-pass metabolism and thus has a higher oral bioavailability (38.3% vs. ramelteon’s 1.8%) (4, 8).

In a study of Non-24 afflicted patients (n₁ = n₂ = 42) against a placebo over 26 weeks, it was found that the most common adverse effects of this drug include headaches, nightmares and abnormal dreams, disturbed sleep, and drowsiness. Also notable was an increased liver enzyme (alanine aminotransferase) concentration in the blood. Use in subjects with mild to moderate hepatic impairment is safe without dose adjustments, but use accompanying severe impairment is not advised due to a lack of testing (4).

Although the approximate number of patients of Hetlioz® is relatively low, the drug’s high cost of about $14,000 - $15,000 for one month’s supply counteracts the small market. Its net product sales grew to $28 million in the second quarter of 2018, up 10% from the first quarter ($25.4 million) and up 25% from the fourth quarter of 2017 ($22.5 million); total net product sales for Vanda Pharmaceuticals was $47.4 million during the same period (13).

Since its approval by the FDA, controversy has surrounded Hetlioz® regarding its Phase III trials, unexplained label changes, and misleading public statements. One advocacy group in particular, Public Citizen, with “more than 350,000 members and supporters nationwide,” wrote a petition to the FDA demanding: 1.) Revision of “Indications and Usage” to align with indication proposed in NDA 205677; 2.) Revision of “Carcinogenesis,” “Mutagenesis,” and “Pregnancy” sections to include information released by FDA that wasn’t labeled; 3.) Distribution of medication guide to bring attention to these newly-labeled indications and risks; 4.) Distribution of “Dear Doctor” letter notifying physicians of corrected information; 5.) Conduction of “large, adequately powered postmarketing clinical trial to obtain more robust safety data in this patient population, for which the drug was originally approved” (6). Of the more egregious offenses, according to the advocacy group, was the removal of the phrase “in blind patients without light perception” in the “Indications and Usage” section. They claimed that this was wrongfully misleading the public to believe that the medication was suitable for the non-blind as well as the blind, thus expanding the range of possible patients. However, the FDA had previously clarified that the drug was to be approved for both sighted and non-sighted individuals.

            Interestingly enough, the drug has recently undergone numerous other studies to further examine its effects on insomnia, which was one of its first primary targets back in its early years of testing. Vanda Pharmaceuticals is also currently conducting studies concerning tasimelteon’s effects on jet lag disorder and Smith-Magenis Syndrome (11, 5).Though similar to its current use, this shows the fluidity of the entire drug discovery and development process; one may find that a certain drug more effectively combats a different affliction than planned, and even more uses for a drug can be discovered and investigated even long after its approval and commercialization.

References

1. “Drugs@FDA: FDA Approved Drug Products.” Accessdata.fda.gov, USFDA, www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process.

2. “Generic TASIMELTEON Entry, Pharmaceutical Patent Expiration Information and Freedom to Operate.” Deep Knowledge on Small-Molecule Drugs and the Global Patents Covering Them, ThinkBiotech LLC, www.drugpatentwatch.com/p/generic-api/tasimelteon.

3. “Hetlioz (Tasimelteon) for the Treatment of Non-24-Hour Sleep-Wake Disorder.” Drug Development Technology, Verdict Media Ltd., 2018, www.drugdevelopment-technology.com/projects/hetlioz-tasimelteon-treatment-non-24-hour-sleep-wake-disorder/.

4. “Hetlioz (Tasimelteon): Side Effects, Interactions, Warning, Dosage & Uses.” RxList, www.rxlist.com/hetlioz-drug.htm.

5. “Investor Relations.” VandaPharma.com, Vanda Pharmaceuticals, Inc., phx.corporate-ir.net/phoenix.zhtml?c=196233&p=irol-news&nyo=0.

6. Petition to the FDA on Tasimelteon. Public Citizen, 11 June 2015, www.citizen.org/sites/default/files/2265.pdf.

7. Rivara, Silvia, et al. “Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders.” Current Topics in Medicinal Chemistry, vol. 8, no. 11, 2008, pp. 954–968., doi:10.2174/156802608784936719.

8. “Rozerem (Ramelteon): Side Effects, Interactions, Warning, Dosage & Uses.” RxList, www.rxlist.com/rozerem-drug.htm.

9. “Search of: Tasimelteon - List Results.” ClinicalTrials.gov, clinicaltrials.gov/ct2/results?cond=&term=tasimelteon&cntry=&state=&city=&dist=.

10. “TASIMELTEON.” LiverTox | National Institutes of Health, U.S. Department of Health and Human Services, livertox.nih.gov/Tasimelteon.htm.

11. “Tasimelteon.” National Center for Biotechnology Information. PubChem Compound Database, U.S. National Library of Medicine, pubchem.ncbi.nlm.nih.gov/compound/Tasimelteon#section=Top.

12. Torres, Rosarelis, et al. “Absolute Bioavailability of Tasimelteon.” American Journal of Therapeutics, vol. 22, no. 5, 2015, pp. 355–360., Accessed via: https://journals.lww.com/americantherapeutics/Fulltext/2015/09000/Absolute_Bioavailability_of_Tasimelteon.5.aspx.

13. Vanda Pharmaceuticals Inc. “Vanda Pharmaceuticals Reports Second Quarter 2018 Financial Results.” PR Newswire, PR Newswire Association LLC, 1 Aug. 2018, www.prnewswire.com/news-releases/vanda-pharmaceuticals-reports-second-quarter-2018-financial-results-300690517.html.

14. Williams, Wilbur P., et al. “Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders.” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, vol. 36, no. 9, 2016, pp. 1028–1041. Accessed via: https://onlinelibrary.wiley.com/doi/pdf/10.1002/phar.1822.