Friday, October 26, 2018

Ramelton



Rozerem (Ramelteon)
By Jack Keady
1. Back Ground

            Insomnia is a neurological disorder that causes difficulty falling asleep, staying a sleep, or negatively effects the overall quality of a person’s sleep. Ramelteon, which is structurally based on the naturally occurring melatonin, is a FDA approved drug that helps people diagnosed with insomnia.1 Melatonin, which is produced by the pineal gland, reaches peak synthesis and release at night, which helps lead to sleep.2 Melatonin has been explored as a sleep aid, but its half-life is very low, due to how quickly it is broken down in the liver, which means the drug peaks only after an hour to 90 minutes depending on dose.2 The bioavailability, or amount of the drug that enters circulation, of melatonin also varied widely for a single dose.2 The inconsistencies of pure melatonin lead to a desire for a more stable melatonin derivative to help people affected by insomnia.

2. Synthesis and Drug Target

            Ramelteon, which’s brand name is Rozerem, was synthesized in a series of experiments conducted by the Pharmaceutical Research Division of Takeda Chemical Industries. The experiments were trying to synthesize a compound with strong affinity for the MT1 receptor, and acted as an antagonist for this receptor.3 MT1 is one of the receptors melatonin binds to decreases wakefulness.3 The compound also needed to show no affinity to other receptors, such as the MT3, because at the time of the study it was unknown what purpose the MT3 receptor served.3

            Multiple compounds were synthesized from preexisting synthetic compounds, which were then tested for MT1 affinity in Chinese Hamster Ovary cells expressing the desired receptor, MT3 affinity in Syrian hamster brains and peripheral organs, and overall efficacy in freely moving cats.3 It was found that the compound (S)-(-)-22b was the most potent and selective antagonist to the MT1 receptor, which would later become known as Ramelton.3 While the drug was designed to be selective for the MT1 receptor, it has also shown a selectivity for the MT2 receptor in the brain.3

3. FDA Approval

            The FDA approved Takeda Pharmaceutical’s new drug application for an 8mg Rozerem pill on 07/22/2005.4 Rozerem originally was granted an indication for the treatment of insomnia that is described as difficulty with the onset of sleep.5 Clinical trials were conducted for both chronic and transient insomnia.6 A group of 405 healthy 18-64 year olds with chronic insomnia underwent a double-blind placebo test where the efficacy of 8-mg and 16-mg dozes of Rozerem were tested against a placebo. The latency to persistent sleep was measured with polysomnography, and it was found that 8-mg was efficacious, but 16-mg was not.6 A similar study was conducted with 100 people, 65 years and older who have chronic insomnia, with 4-mg and 8-mg of Rozerem, and both dozes were efficacious.6 For transient insomnia 289 healthy adults between 18-64 underwent a double blind, randomized placebo test, of 8-mg and 16-mg doses of Rozerem. The 8-mg dose was found efficacious using polysomnography.6 All tests were conducted in the United States.6

3.1 Adverse Reactions

            There are a number of adverse reactions that were reported during the clinical study. People reported: headaches, somnolence, fatigue, dizziness, nausea, worsening insomnia, upper respiratory tract infection, diarrhea, myalgia, depression, dysgeusia, anthralgia, influenza, and decreased blood cholesterol.5 These are listed in order of prevalence with headache being the most at 7%.5

            Elderly patients could also be at an increased risk for adverse reactions. A study found that elderly patients experienced a higher maximum concentration, a longer half-life, and lower clearance of the drug.7 While this didn’t have any major pharmacokinetic implications, the increased concentration and lower clearance could lead to prolonged and adverse effects in the elderly.7

3.1 Food

             Rozerem has a low bioavailability, which can be significantly decreased if it is taken with food.7 The maximum concentration is lowered and the time to reach that concentration is increased if taken after eating a high fat meal.7


3.2 Overdose and Dependency

             In the animal studies conducted there was no signs of the development of dependency. Primates did not self-administer the drug given the opportunity.5 There were no physical signs of overdose when up to 160 mg, 20 times the daily dose, was administered during animal trials.5
           
3.3 Drug interactions

            CYP1A2 is the major enzyme in the metabolism of Rozerem, with CYP2C and CYP3A4 also contribute to the metabolism.6 Rozerem should not be taken with medication that inhibits these enzymes, such as fluvoxamine, roframpin, ketoconazole, and fluconazole.6 There were no recorded significant clinical interactions between alcohol and Rozerem, but alcohol inhibits deep REM sleep, which is the indication of Rozerem.6 For this reason Rozerem should not be taken with alcohol.

4. Takeda Pharmaceutical Company Limited

            Takeda Pharmaceutical Company Limited is headquartered in Japan and in 2017 brought in 1711.1 Bn ¥, about $16 Bn USD.8 Rozerem brought in 17.6 Bn ¥, about $160 million USD, which is approximately 1% of total revenue.8 Takeda is the sole producer of Ramelteon, the active agent in Rozerem.9 Takeda received the US patent in 2000, and was rewarded the rights to the drug and multiple methods of using a MT1 agonist as a treatment for insomnia, circadian rhythm regulation, time zone change syndrome, and others.9
           
           
5. Market

            Insomnia has a large economic impact in the United States. It is estimated that 22.1% of adults suffer from chronic insomnia according to the DSM-IV definition.10 This large population costs an aggregate $100 billion USD a year in both direct costs of treatment and indirect costs such as lost productivity.10 Currently Rozerem is sold at an average of $15.11 a pill, which is competitive with other popular sleep aids such as Ambien.11 Rozerem has a major advantage to many other insomnia medications in the market place. Because Rozerem targets the MT1 receptor, and not the GABA receptors there is a significantly lower risk of abuse than benzodiazepine sleep aids.7 The only other MT1 receptor agonist in the market now is Hetlioz (tasimelteon), which is mostly prescribed for people with Non-24-hour sleep-wake disorder (Non-24). [12][13] While Hetlioz has the same mechanism of action, the medical indication for Hetioz is Non-24, which predominately effects blind individuals and doesn’t represent a large portion of the insomnia medication market. [13][14]

            Despite the large insomnia market, Takeda is not emphasizing Rozerem as an area of growth.8 As mentioned before Rozerem generated 17.6 Bn ¥ of revenue in the 2017 fiscal year, which is a 0.7 % decrease compared to 2016.8 While not explicitly stated in the financial report, Takeda is most likely moving away from Rozerem because their patent expire June 2019.15 Two companies, Dr. Reddy’s Lab SA and ACTAVIS Labs FL INC, have generic forms of Ramelteon approved by the FDA, which leaves little reason for Takeda to emphasize Rozerem as a revenue stream in the future.[16][17]























References

1. Buysse D, Bate G, Kirkpatrick P. Ramelteon. Nature Reviews Drug Discovery. 2005,4:881-882.
2. Brzezinski A. Melatonin in Humans. The New England Journal of Medicine. 1997;336:186-195. doi: 10.1056/NEJM199701163360306
3. Uchikawa O, Fukatsu K, Tokunoh R, et al. Synthesis of Tricyclic Indan Derivatives as Melatonin Receptor Agonists. Journal of Medicinal Chemistry. 2002;45(19):4222-4239. doi: 10.1021/jm0201159
4. Department of Heath & Human Services. (2005). NDA 21-782 Approval. Rockville, MD: Food and Drug Administration
5. Center for Drug Evaluation and Research. (2005). Application Number: 21-782, Approved Labeling. Food and Drug Administration
6. Center for Drug Evaluation and Research. (2005). Application Number: 21-782, Medical Review. Food and Drug Administration
7. Schroeck JL, Ford J, Conway EL, et al. Review of Safety and Efficacy of Sleep Medicines in Older Adults. Clinical Therapeutics. 2016; 38(11):2340-2372. doi: https://doi.org/10.1016/j.clinthera.2016.09.010
8. Weber C, Sraoukos C, Iwasaki M, Plump A. Strategic Focus & Superior Execution FY2017 Annual Results. Takeda Pharmaceutical Company Limited. 2018. Retrieved from:
https://www.takeda.com/siteassets/system/investors/report/quarterlyannouncements/fy2017/fy2017-full-year-results/qr2017_q4_p01_en.pdf
9. United States Patent. (2000). Patent number: 6,034,239
10. Wickwire E, Shaya F, Scharf S. Health economics of insomnia treatments: The return on investment for a good night's sleep. Sleep Medicine Reviews. 2015, 30:72-82.
doi: http://dx.doi.org/10.1016/j.smrv.2015.11.004
11. Information for Vermont Prescribers of Prescription Drugs: (Long Form). Takeda Pharmaceutical Company Limited. 2018
12. Food and Drug Administration Established Pharmacologic Class (EPC) Text Phrase. FDA. 2016. Retrieved from:
13. Hetlioz Full Prescribing Information. FDA, 2014. Refernce ID: 3672439
14. American Academy of Sleep Medicine. ICSD - International classification of sleep disorders, revised: Diagnostic and coding manual. American Academy of Sleep Medicine, 2001.
15. Food and Drug Administration. (2016). Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, Patent and Exclusivity for: N021782. Retrieved from: https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&Appl_No=021782&Appl_type=N
16. Food and Drug Administration. (2015) Drugs@FDA: FDA Approved Drug Products. Retrieved from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=091610
17. Food and Drug Administration. (2013) Drugs@FDA: FDA Approved Drug Products. Retrieved from:

1 comment:

  1. WHat is the size of the market (in Dollars)? Are there any recent new patents for combination drugs or new formulations? Any warning letters for current manufacturers?

    ReplyDelete