| 词条 | Ozanimod |
| 释义 |
| drug_name = | IUPAC_name = 5-(3(1S)-1-[(2-Hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile | image = Ozanimod.svg | width = 285 | image2 = Ozanimod ball-and-stick model.png | alt = | caption = | tradename = | Drugs.com = | MedlinePlus = | pregnancy_AU = | pregnancy_AU_comment = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_AU_comment = | legal_CA = | legal_NZ = | legal_UK = | legal_US = | legal_UN = | legal_status = Investigational | routes_of_administration = | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = 19 hours | duration_of_action = | excretion = | CAS_number = 1306760-87-1 | ATCvet = | ATC_prefix = L04 | ATC_suffix = AA38 | PubChem = 52938427 | DrugBank = DB12612 | ChemSpiderID = 34979946 | UNII = Z80293URPV | KEGG = D10968 | synonyms = RPC1063 | chemical_formula = | C=23 | H=24 | N=4 | O=3 | molecular_weight = 404.46 g/mol | SMILES = CC(C)Oc1ccc(cc1C#N)c2nc(no2)c3cccc4c3CC[C@@H]4NCCO | StdInChI = 1S/C23H24N4O3/c1-14(2)29-21-9-6-15(12-16(21)13-24)23-26-22(27-30-23)19-5-3-4-18-17(19)7-8-20(18)25-10-11-28/h3-6,9,12,14,20,25,28H,7-8,10-11H2,1-2H3/t20-/m0/s1 | StdInChIKey = XRVDGNKRPOAQTN-FQEVSTJZSA-N }}Ozanimod (RPC-1063) is an investigational immunomodulatory drug currently in phase III clinical trials for the therapy of relapsing multiple sclerosis (RMS) and ulcerative colitis (UC).[1] It acts as a sphingosine-1-phosphate (S1P) receptor agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.[1] Shortly after Receptos, Inc. developed ozanimod, they were acquired by Celgene for $7.2 billion.[2] PharmacologyPharmacodynamicsOzanimod is an agonist of the S1P1 and S1P5 receptors.[1] It demonstrates this effect in a dose-dependent manner, with 10-fold potency to three comparators.[1] This is an improvement of selectivity over its predecessor, fingolimod, which is non-specific to all 5 isotypes.[1] The agonism of S1P directly causes its internalization and degradation through the ubiquitin-proteosome pathway.[3] The loss of S1P leads to a decrease in the total lymphocyte count in circulation, specifically CD4+ CCR7+ and CD8+ CCR7+ T cells.[1][4] PharmacokineticsOzanimod has a high oral bioavailability, a circulating half-life of about 19 hours, and reaches highest blood plasma concentrations after about 6 hours.[1][4] Ozanimod is dehydrogenated by two CYP enzymes into two active metabolites, all with similar pharmacokinetics.[4] The decrease in lymphocyte count lasts for approximately 14 days after treatment discontinuation.[4] Unlike fingolimod, it does not require phosphorylation for activation, nor does it demonstrate cardiac abnormalities or hepatotoxicity.[1] Clinical trialsTouchstoneTouchstone is a double-blind, placebo controlled phase II clinical for the treatment of ulcerative colitis. ([https://clinicaltrials.gov/ct2/show/NCT01647516?term=NCT01647516&rank=1 NCT01647516]).[5][6] 197 patients, ages 18–75, with moderate to severe UC (Mayo Score 6-10) were recruited and assigned either placebo, 0.5 mg or 1 mg of oral ozanimod followed by 1 week of dose escalation. The 1 mg dose showed a slight increase in rate of clinical remission of UC and total lymphocyte decrease as compared to the placebo, with the most common adverse effects being headaches and anemia.[5] The authors noted that limitations on this study included a brief duration and small sample size, meaning they could not assess safety nor efficacy.[5] RadianceRadiance is a double-blind, placebo controlled phase combined II/III clinical trial for the treatment of relapsing multiple sclerosis ([https://clinicaltrials.gov/ct2/show/NCT01628393 NCT01628393]).[7][8] For the phase II trial, 258 patients, ages 18–55 with RMS (Mean Expanded Disability Status Scale of 2.9) were assigned either placebo, 0.5 mg or 1 mg of oral ozanimod followed by 1 week of dose escalation.[7] Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis over a period of 24 weeks.[7] Both doses of ozanimod reached anticipated range of 60-70% decreased lymphocyte count, and were well tolerated, with a safety profile consistent with a previous phase 1 study in healthy volunteers.[7][9] The most common adverse effects as compared to the placebo were: nasopharyngitis, headache, and urinary-tract infections, with no serious infectious or cardiac adverse effects.[7] With these results, both doses of ozanimod were taken forward into the 2-year long phase III trial and is completed but unpublished as of November 2016.[7][8] SunbeamSunbeam is the second RMS phase III clinical trial to establish the dose with optimum safety-benefit relationship, with an estimated size of 1200 patients ([https://clinicaltrials.gov/ct2/show/study/NCT02294058?view=record NCT02294058]).[7][10] It began in November 2014 and has an estimated completion date of February 2017.[10] CommercialAfter going public in May 2013, Receptos, Inc. stock surged with the clinical data ozanimod displayed as a S1P immunomodulating drug.[11][12] In August 2015, Receptos was acquired by Celgene for $7.2 billion through a combination of cash in hand and new debt, leading to a 22% increase in their stock value.[2][13] Receptos, Inc. (Celgene) patented the synthesis of ozanimod in July 2016.[14] With the expansion of Celgene's inflammation and immunology profile, the company had been expecting to generate $4 to $6 billion in annual sales from ozanimod; however, the FDA rejected its application for the drug's approval in February 2018.[12][15][16] References1. ^1 2 3 4 5 6 7 {{Cite journal|last=Scott|first=F L|last2=Clemons|first2=B|last3=Brooks|first3=J|last4=Brahmachary|first4=E|last5=Powell|first5=R|last6=Dedman|first6=H|last7=Desale|first7=H G|last8=Timony|first8=G A|last9=Martinborough|first9=E|date=2016-06-01|title=Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity |journal=British Journal of Pharmacology |language=en|volume=173|issue=11|pages=1778–1792|doi=10.1111/bph.13476|issn=1476-5381|pmc=4867749|pmid=26990079}} 2. ^1 {{cite web|title=Celgene Press Release|url=http://ir.celgene.com/releasedetail.cfm?releaseid=922090}} 3. ^{{cite journal|last1=Jo|first1=E.|title=S1P1-selective in vivo-active agonists from high- throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate|journal=Chemical Biology|date=2005|volume=12|issue=6|pages=703–715|doi=10.1016/j.chembiol.2005.04.019|pmid=15975516|url=https://scholar.google.com/scholar_url?url=http://www.sciencedirect.com/science/article/pii/S107455210500133X&hl=en&sa=T&oi=gsb-ggp&ct=res&cd=0&ei=ug0hWIKmAYusmgGP_oyQBg&scisig=AAGBfm2bQxgYK88xBDi1loE-_ceWAZXNdQ}} 4. ^1 2 3 {{cite journal|last1=Juif|first1=P-E.|title=Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators|journal=Expert Opinion on Drug Metabolism & Toxicology |date=2016|volume=5255|issue=8|pages=879–895 |doi=10.1080/17425255.2016.1196188|pmid=27249325}} 5. ^1 2 {{cite journal|date=2016|title=Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis|journal=New England Journal of Medicine|volume=374|issue=18|pages=1754–62|doi=10.1056/NEJMoa1513248|pmid=27144850|last1=Sandborn|first1=W.}} 6. ^{{cite web|title=Efficacy and Safety Study of RPC1063 in Ulcerative Colitis|url=https://clinicaltrials.gov/ct2/show/NCT01647516?term=NCT01647516&rank=1|website=ClinicalTrials.gov}} 7. ^1 2 3 4 5 6 {{Cite journal|last=Cohen|first=Jeffrey A|last2=Arnold|first2=Douglas L|last3=Comi|first3=Giancarlo|last4=Bar-Or|first4=Amit|last5=Gujrathi|first5=Sheila|last6=Hartung|first6=Jeffrey P|last7=Cravets|first7=Matt|last8=Olson|first8=Allan|last9=Frohna|first9=Paul A|title=Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial|url=http://linkinghub.elsevier.com/retrieve/pii/S1474442216000181|journal=The Lancet Neurology|volume=15|issue=4|pages=373–381|doi=10.1016/s1474-4422(16)00018-1|pmid=26879276|year=2016}} 8. ^1 {{Cite web|url=https://clinicaltrials.gov/ct2/show/NCT01628393|title=Efficacy and Safety Study of RPC1063 in Relapsing Multiple Sclerosis Patients (Radiance Study) - Full Text View - ClinicalTrials.gov|last=|first=|date=|website=clinicaltrials.gov|publisher=|access-date=}} 9. ^{{Cite web|url=http://www.investorvillage.com/uploads/86668/files/Poster4.pdf|title=Results of a Thorough QT/QTc (TQT) Study of Orally Administered RPC1063, a Novel, Selective S1P1 Receptor Agonist, in Healthy Adult Volunteers|last=Hartung|first=J.|date=2012|publisher=|access-date=}} 10. ^1 {{Cite web|url=https://clinicaltrials.gov/ct2/show/NCT02294058|title=Phase 3 Study of RPC1063 in Relapsing MS - Full Text View - ClinicalTrials.gov|website=clinicaltrials.gov|access-date=2016-11-09}} 11. ^{{cite news|title=Celgene Agrees to $7.2 Billion Deal for Receptos|url=https://www.nytimes.com/2015/07/15/business/dealbook/celgene-agrees-to-7-2-billion-deal-for-receptos.html?_r=0|newspaper=New York Times|date=2015-07-14|last1=Pollack|first1=Andrew}} 12. ^1 {{cite web|title=Celgene 2015 Annual Report|url=http://files.shareholder.com/downloads/AMDA-262QUJ/3100938083x0x889847/98954B20-BFA0-4AD4-9649-105595A19800/Celgene_2015_Annual_Report.pdf}} 13. ^{{cite news|title=Celgene to Buy Receptos for $7.2 Billion|url=https://www.wsj.com/articles/celgene-to-buy-receptos-for-about-7-2-billion-1436908831|publisher=Wall Street Journal|date=July 14, 2015}} 14. ^{{cite web|url=http://pdfpiw.uspto.gov/.piw?Docid=09388147&homeurl=http%3A%2F%2Fpatft.uspto.gov%2Fnetacgi%2Fnph-Parser%3FSect1%3DPTO2%2526Sect2%3DHITOFF%2526p%3D1%2526u%3D%25252Fnetahtml%25252FPTO%25252Fsearch-adv.htm%2526r%3D4%2526f%3DG%2526l%3D50%2526d%3DPTXT%2526S1%3Dreceptos%2526OS%3Dreceptos%2526RS%3Dreceptos&PageNum=&Rtype=&SectionNum=&idkey=NONE&Input=View+first+page|title=SELECTIVE SPHINGOSINE 1 PHOSPHATE RECEPTOR MODULATORS AND METHODS OF CHIRAL SYNTHESIS|last=|first=|date=July 12, 2016|website=U.S. Patent & Trademark Office|publisher=|access-date=}} 15. ^{{cite web|title=Celgene to Acquire Receptos for $7.2B|url=http://www.genengnews.com/gen-news-highlights/celgene-to-acquire-receptos-for-7-2b/81251504|website=Genetic Engineering & Biotechnology News|date=2015-07-14}} 16. ^{{Cite news|url=https://www.reuters.com/article/us-celgene-fda/u-s-fda-rejects-filing-for-celgene-ms-drug-shares-fall-idUSKCN1GB30U|title=U.S. FDA rejects filing for Celgene MS drug, shares fall|last=Editorial|first=Reuters|work=U.S.|access-date=2018-03-28|language=en-US}} 7 : Immunomodulating drugs|Indanes|Nitriles|Oxadiazoles|Isopropyl compounds|Ethanolamines|Phenol ethers |
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