Tasimelteon

Tasimelteon

Systematic (IUPAC) name
(1R, 2R)-N-[2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide
Clinical data
Trade names	Hetlioz
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	not determined in humans
Protein binding	89–90%
Metabolism	extensive hepatic, primarily CYP1A2 and CYP3A4-mediated
Biological half-life	0.9–1.7 h / 0.8–5.9 h (terminal)
Excretion	80% in urine, 4% in feces
Identifiers
CAS Number	609799-22-6 Y
ATC code	N05CH03 (WHO)
PubChem	CID: 10220503
IUPHAR/BPS	7393
ChemSpider	8395995 N
UNII	SHS4PU80D9 Y
ChEBI	CHEBI:79042 N
Chemical data
Formula	C15H19NO2
Molecular mass	245.32 g/mol
SMILES CCC(=O)NC[C@@H]1C[C@H]1C2=C3CCOC3=CC=C2
InChI InChI=1S/C15H19NO2/c1-2-15(17)16-9-10-8-13(10)11-4-3-5-14-12(11)6-7-18-14/h3-5,10,13H,2,6-9H2,1H3,(H,16,17)/t10-,13+/m0/s1 N Key:PTOIAAWZLUQTIO-GXFFZTMASA-N N
NY (what is this?)  (verify)

Tasimelteon (trade name Hetlioz) is a drug approved by the U.S. Food and Drug Administration (FDA) in January 2014 for the treatment of non-24-hour sleep–wake disorder (also called Non-24, N24 and N24HSWD). In June 2014, the European Medicines Agency accepted an EU filing application for tasimelteon and in July 2015, the drug was approved in Europe for the treatment of non-24-hour sleep-wake rhythm disorder in totally blind adults, but not in the rarer case of non-24 in sighted people.

Tasimelteon is a selective agonist for the melatonin receptors MT₁ and MT₂, similar to other members of the melatonin receptor agonist class of which ramelteon (2005) and agomelatine (2009) were the first approved. As a treatment for N24HSWD, as with melatonin or other melatonin derivatives, the patient may experience improved sleep timing while taking the drug. Reversion to baseline sleep performance occurs within a month of discontinuation.

Development

Tasimelteon (previously known as BMS-214,778) was developed for the treatment of insomnia and other sleep disorders. A phase II trial on circadian rhythm sleep disorders was concluded in March 2005. A phase III insomnia trial was conducted in 2006. A second phase III trial on insomnia, this time concerning primary insomnia, was completed in June 2008. In 2010, the FDA granted orphan drug status to tasimelteon, then regarded as an investigational medication, for use in totally blind adults with N24HSWD. (Through mechanisms such as easing the approval process and extending exclusivity periods, orphan drug status encourages development of drugs for rare conditions that otherwise might lack sufficient commercial incentive.)

On completion of Phase III trials, interpretations of the clinical trials by the research team concluded that the drug may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders. A year-long (2011–2012) study at Harvard tested the use of tasimelteon in blind subjects with non-24-hour sleep-wake disorder. The drug has not been tested in children nor in any non-blind people.

FDA approval

In May 2013 Vanda Pharmaceuticals submitted a New Drug Application to the Food and Drug Administration for tasimelteon for the treatment of non-24-hour sleep–wake disorder in totally blind people. It was approved by the FDA on January 31, 2014 under the brand name Hetlioz. In the opinion of an advocacy group Public Citizen, the FDA erroneously allowed it to be labelled without stating that is only approved for use by totally blind people. However, FDA updated its press release on Oct. 2, 2014 to clarify the approved use of Hetlioz, which includes both sighted and blind individuals. The update did not change the drug labeling (prescribing information).

Toxicity

Experiments with rodents revealed fertility impairments, an increase in certain cancers, and serious adverse events during pregnancy at dosages in excess of what is considered the "human dose".

See also

• Discovery and development of melatonin receptor agonists