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.

Doxazosin: The Past Drug

Doxazosin is a drug developed to help with mild to severe hypertension as well as to ease prostate muscle contractions. Both problems are an indirect effect of over stimulation of one or multiple of the three α₁-adrenoceptors. To solve this problem a synthetic or natural, synthetic in this case, compound had to be developed that would inhibit the activity of the α₁-adrenoceptors. The process to make the specific antagonist is outlined in a span of nine pages which boils down to an extensive synthesis of minimally twelve steps. These steps utilize several of the same compounds with varying R-groups branched off them that change the structure of the base compound. Several methods including HPLC, LC-MS, UV spectrophotometry and HPTLC3,4,5,6 were used to determine the final pharmaceutical formulation. UV spectrophotometry was the main determinate in dosage for pharmaceutical use. Absorbance values for several dosages were observed in human liver cells and half-lives helped to determine the dosage that would stay in the body for the correct amount of time.

Three alpha-blockers or antagonists were developed and FDA-approved prior to doxazosin. They mostly were targeted for the first of the three receptors as this is accepted as the primary receptor associated with prostate smooth muscle contraction. These included the nonselective phenoxybenzamine (which inhibited all of the α₁-adrenoceptors), short-acting selective prazosin, and lastly the long-lasting and selective terazosin. Comparatively to the last of these, doxazosin has a significantly longer half-life while keeping the selectivity of terazosin as well. Similarly, all of these drugs were developed as a drug to be used with several others as well to work together. Doxazosin before being replaced also went through extensive clinical trials in order to develop a way to orally take the compound. The polymer that was found suitable to coat the tablet was Eudragit powdered E-100. However, a major flaw with the doxazosin drug is that it has little to no feedback control. This means that because it is an antagonistic drug, it does not produce any product that will go back and limit the effect of the drug. This coupled with the fact it has a long half-life means that even though the needed effects stay for a long time so do adverse effects. These include low blood pressure, dizziness, shortness of breath, tiredness, abdominal pain, diarrhea, headache, and swelling caused by the inhibition of the α₁-adrenoceptors. Doxazosin had less of a correlation with these side effects than the first two inhibitors developed however was more likely to cause these than terazosin and therefore was not used long.

The regulation and testing of doxazosin is very minimal in information because it is the fifth alpha blocker developed in its class. This means that the developers of this drug did not need to go through most of the  beginning trials as long as they could prove that this drug has the same effects and target as the previous drugs developed. However, many later clinical trials and some animal testing had to be conducted in order to prove the viability of this advanced version. Also, due to stricter laws in foreign countries regarding the distribution of pharmaceuticals, places such as the European Union are still continuing clinical trials for the base line drug combined with other medications and with slight modifications. Trials conducted using animal test subjects such as dogs and rats resulted in the formation of myocardial fibrosis within months of administering the drug. Nothing similar to these results was proven to happen in human trials. Pregnant women are advised to be cautious and consult a doctor before taking doxazosin, but trials show that radioactivity passed through the placenta with no adverse effects. Trials were not conducted on children below the age of 12 and therefore they are cautioned against taking the drug. The largest concern through all human trials was the result of BPH or benign prostate hyperplasia and slight concerns over increased hypertension. No overdoses occurred during any trial and therefore max doses were not determined prior to prescribing only a correct dosage.

The drug was originally manufactured, patented and distributed by Pfizer pharmaceuticals. They still today sell the synthetic compound under the name of Cardura and Cardura XL. These titles are both copyrighted to the Pfizer company and there are several general names for the pharmaceutical. The first patent was developed in 1985 by Edwards K David under the administration of Pfizer. Today there have been over 208 patents using doxazosin whether by itself or with other compounds and 9 of them belong to Pfizer, and 7 to David.

After the drug completed clinical trials its sales reached a peak point around the end of 1999 leading into the first two quarters of the 2000 financial year. They then soon declined to $552 million from $795 million between the single year following into 2001. This is shown by a 22% decrease of all alpha-blocker sales in the most previous years.

Lepor, Herbert. “The Evolution of Alpha-Blockers for the Treatment of Benign Prostatic Hyperplasia.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, 2006, www.ncbi.nlm.nih.gov/pmc/articles/PMC1765042/.

Carolina GonçalvesPupe,Flávia AlmadaDo Carmo,Valéria PereiraDe Sousa1MarleneLopes,BárbaraAbrahim-Vieira1António JoséRibeiro,FranciscoVeiga,Carlos RangelRodrigues,CristinaPadula,PatriziaSanti,Lucio MendesCabral. “Development of a Doxazosin and Finasteride Transdermal System for Combination Therapy of Benign Prostatic Hyperplasia.” NeuroImage, Academic Press, 31 Dec. 2015, www.sciencedirect.com/science/article/pii/S0022354915308406.

Chung, M, et al. “Clinical Pharmacokinetics of Doxazosin in a Controlled-Release Gastrointestinal Therapeutic System (GITS) Formulation.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, Nov. 1999, www.ncbi.nlm.nih.gov/pmc/articles/PMC2014349/.

Elliott, H L, et al. “Pharmacokinetic Overview of Doxazosin.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, 29 May 1987, www.ncbi.nlm.nih.gov/pubmed/2884857.

“Doxazosin.” DrugBank, www.drugbank.ca/drugs/DB00590.

“US5919931A - Process for the Manufacture of Intermediates Suitable to Make Doxazosin, Terazosin, Prazosin, Tiodazosin and Related Antihypertensive Medicines.” Google Patents, Google, patents.google.com/patent/US5919931?oq=5919931.

Jayapal, M. R., et al. “Analytical Method Development and Validation of Doxazosin Mesylate Uncoated Tablets by RP-HPLC.” International Journal of Biomedical Research, vol. 4, no. 9, 2013, p. 465., doi:10.7439/ijbr.v4i9.306.

Pollack, Andrew. “A Big Hypertension Study, and Its Minimal Impact.” The New York Times, The New York Times, 27 Nov. 2008, www.nytimes.com/2008/11/28/business/28govtest.html.

“Clinical Trials for Doxazosin.” Clinical Trials Register, www.clinicaltrialsregister.eu/ctr-search/search?query=doxazosin.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019668s021lbl.pdf

Ondansetron

Ondansetron

Ondansetron was invented in the 1980’s in an English laboratory affiliated with the pharmaceutical company GlaxoSmithKline (GSK) The FDA approved ondansetron in January of 1991 under the name Zofran, and the generic ondansetron hit the market in the United States in 2007 (Brodhead). Zofran is primarily used to prevent nausea and vomiting due to chemotherapy, radiation treatment, or anesthetics (Cunha). Ondansetron has also shown to be effective in treating various other ailments including irritable bowel syndrome, vertigo, drug withdrawal, depression, and chronic diarrhea.

Ondansetron is a 5-hydroxytryptamine₃ (5-HT₃) antagonist. 5-HT, a monoaminergic neurotransmitter, helps control many physiological functions such as contraction and relaxation in muscles in respiratory and gastrointestinal systems, mood changes, and sleep induction. Ondansetron targets 5-HT-rich areas of the body to prevent vomiting from occurring. Ondansetron also affects the central nervous system and encourages cells to release dopamine, which helps block the 5-HT receptors from acting (Ye et al).

Available to be administered orally or via injection, ondansetron is a hydrochloride dehydrate base. The drug is absorbed easily and can be taken with food or antacids. The half-life of ondansetron is only two to four hours with a clearance rate of 541 mL/min. The adverse effects reported with ondansetron use are mild but common. Patients may have a headache, but this is most commonly found in patients who are prone to migraines or are experiencing caffeine withdrawal due to pre-surgical diet limitations. Some patients may experience an increased heart rate or blood pressure, and fatigue has been noted to be associated with ondansetron. (Ye et al)

An older form of this medication, promethazine, was almost equally as efficient in treating nausea and vomiting in patients. However, promethazine was frequently associated with severe sedation and did not allow patients to continue with their daily routines uninterrupted. Ondansetron is a much weaker sedative and is able to be taken without great risk of sedation. Akathisia was also reported in patients who took promethazine, while ondansetron does not seem to produce this adverse effect (Braude, Crandall)

In 2011, the FDA recalled all 32 mg doses of intravenous Zofran due to cardiac risks. The drug seemed to cause an arrhythmia called AT interval prolongation, which is potentially fatal. GSK was required to begin a study into why the drug was causing this heart rhythm, and the 32 mg dose was taken off the market by 2013 (FDA).

Ondansetron is a popular drug sold by many companies like Teva, Hospira, and Pfizer, and it is available in almost all pharmacies. It is a relatively low cost drug, available for just under 10 USD, while the name brand Zofran can cost hundreds of dollars without health insurance. Currently, several patents are under review for various ways of administering ondansetron. A research group in America is currently trying to make an aerosol version of ondansetron that can be administered as a mouth spray. This form of ondansetron would have a stable shelf life and a quick response time (Vangara et al). Another researcher in China has invented a type of “water-free swallowing granule” that tastes better and is more digested (Gongye).

Ondansetron is currently not approved for treatment of morning sickness in pregnant women. The issue arises in that ondansetron may cause birth defects, but tests are still being run to produce reliable results (Brodhead).

Works Cited

Braude, D, and C Crandall. “Ondansetron versus Promethazine to Treat Acute Undifferentiated Nausea in the Emergency Department: a Randomized, Double-Blind, Noninferiority Trial.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, Mar. 2008, www.ncbi.nlm.nih.gov/pubmed/18304050.

Brodhead, Peter J. “The History of Zofran.” Spangenberg Shibley & Liber LLP, 2015, www.spanglaw.com/blog/2015/february/the-history-of-zofran/

Cunha, John. “Ondansetron (Zofran): Side Effects, Dosages, Treatment, Interactions, Warnings.” RxList, 2017, www.rxlist.com/consumer_ondansetron_zofran/drugs-condition.html

“Drug Safety and Availability - FDA Drug Safety Communication: Abnormal Heart Rhythms May Be Associated with Use of Zofran (Ondansetron).” U S Food and Drug Administration Home Page, Center for Drug Evaluation and Research, 2011, www.fda.gov/Drugs/DrugSafety/ucm271913.htm.

“Drug Safety and Availability - FDA Drug Safety Communication: Updated Information on 32 Mg Intravenous Ondansetron (Zofran) Dose and Pre-Mixed Ondansetron Products.” U S Food and Drug Administration Home Page, Center for Drug Evaluation and Research, 4 Dec. 2012, www.fda.gov/Drugs/DrugSafety/ucm330049.htm.

Vangara, et al. “SUBLINGUAL ONDANSETRO SPRAY.” Patentscope.wipo.int, 16 Feb. 2018, patentscope.wipo.int/search/en/detail.jsf?docId=WO2018031292&tab=PCTBIBLIO&office=&prevFilter=&sortOption=Pub%2BDate%2BDesc&queryString=FP%3A%28ondansetron%29&recNum=2&maxRec=478.

Gongye, Xiangxin. “Ondansetron Water-Free-Swallowing Granules.” WIPO - Search International and National Patent Collections, 2018, patentscope.wipo.int/search/en/detail.jsf?docId=CN212110820&tab=NATIONALBIBLIO&office=&prevFilter=&sortOption=Pub%2BDate%2BDesc&queryString=FP%3A%28ondansetron%29&recNum=4&maxRec=478.

Ye, Jiang-Hong, Rex Ponnudurai, and Rebecca Shaefer. “Ondansetron: A Selective 5-HT₃ Receptor Antagonist and Its Applications in CNS-Related Disorders.” CNS Drug Reviews. Vol 7. No. 2. Department of Anesthesiology, UMDNJ, 2001.