Chemistry:Ozanimod

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Short description: Medication
Ozanimod
Ozanimod.svg
Ozanimod ball-and-stick model.png
Clinical data
Trade namesZeposia
Other namesRPC-1063
AHFS/Drugs.comMonograph
MedlinePlusa620029
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life19 hours
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC23H24N4O3
Molar mass404.470 g·mol−1
3D model (JSmol)

Ozanimod, sold under the brand name Zeposia, is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis.[3][4][6][7] It acts as a sphingosine-1-phosphate receptor (S1PR) agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.[6]

The most common adverse reactions are upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.[3][8]

Ozanimod was approved for medical use in the United States in March 2020,[8][9][10] in the European Union in May 2020,[4] and in Australia in July 2020.[1][11]

Medical uses

In the United States, ozanimod is indicated for the treatment of adults with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease; and with moderately to severely active ulcerative colitis.[3]

In the European Union and in Australia, ozanimod is indicated for the treatment of adults with relapsing remitting multiple sclerosis.[11]

Pharmacology

Potency and selectivity

The principle of autoimmune therapy based on targeting S1P receptors was established through the clinical work performed during development of fingolimod (trade name Gilenya), a non‐selective S1P modulator.[12][6][better source needed] The prospects for ozanimod (Scripps-Receptos compound RPC1063) depended upon demonstration of comparable or better activity and selectivity relative to fingolimod and other comparators.[citation needed] During the discovery phase of its development, ozanimod was shown to be a selective agonist of the S1P1 and S1P5 receptors.[6][non-primary source needed] Specifically, in a discovery research report, ozanimod's equal potency and improved selectivity for S1P1 and S1P5 receptor family members were determined though a combination of inhibition, binding, and signalling assays for the S1P1, S1P2, S1P3, S1P4, and S1P5 receptor types alongside the same tests with fingolimod and other compounds.[6][13]

Potency for ozanimod as an agonist of the S1P1 receptor type was established through observed sub-nanomolar EC50 values in GTPγS binding and cAMP inhibition assays, and for the S1P5 type through an observed nanomolar EC50 value in the GTPγS binding assay.[6] Measured alongside its binding to the S1P2, S1P3, and S1P4 receptor types, these concentration-response results supported a conclusion of an improved selectivity profile, with selectivity of S1P1 over S1P5 receptors at 27‐fold, and selectivity for S1P1 over S1P2, S1P3, and S1P4 receptors greater than 10,000‐fold.[6]

Also, these assays allowed comparison of ozanimod potency against and selectivity for S1P1 over other S1 receptors, relative to related S1 active agents siponimod and the phosphorylated (prodrug) forms of fingolimod and mocravimod,[14] where ozanimod was similar to these comparators in S1P1 potency, but had the elevated selectivities stated above (versus fingolimod being potent in stimulating S1P3, S1P4, and S1P5, siponimod potent with a S1P5 form, and mocravimod active in some way against S1P3, S1P4, and S1P5), making its selectivity profile an improvement over all of these.[6]

Hence, the study concluded that it had "established... RPC1063 [as] a potent agonist of the S1P1 receptor with additional agonist activity on the S1P5 receptor" with S1P1 activity "similar to other known, less selective S1P receptor agonists".[6]

Pharmacodynamics and pharmacokinetics

The agonism of S1P directly causes its internalization and degradation through the ubiquitin-proteosome pathway.[15][better source needed] The loss of S1P leads to a decrease in the total lymphocyte count in circulation, specifically CD4+ CCR7+ and CD8+ CCR7+ T cells.[6][16]

Ozanimod has a high oral bioavailability, a circulating half-life of about 19 hours, and reaches highest blood plasma concentrations after about 6 hours.[6][16] Ozanimod is dehydrogenated by two CYP enzymes into two active metabolites, all with similar pharmacokinetics.[16] The decrease in lymphocyte count lasts for approximately 14 days after treatment discontinuation.[16] Unlike fingolimod, it does not require phosphorylation for activation, nor does it demonstrate cardiac abnormalities or hepatotoxicity.[6]

History

Ozanimod was invented by Hugh Rosen, Edward Roberts, and colleagues at The Scripps Research Institute, and was subsequently out-licensed in the creation of the startup, Receptos Inc. [17][18][better source needed][19] Celgene Corp acquired Receptos along with its intellectual property in 2015.[17][20][19] Bristol Myers Squibb acquired Celgene in 2019 (and with it, ozanimod and the rest of its products and pipeline).[21][22][18]

The US Food and Drug Administration (FDA) approved ozanimod based on evidence from two clinical trials (Trial 1/NCT02294058 and Trial 2/ NCT02047734) of 1767 subjects with relapsing forms of multiple sclerosis.[9] The trials were conducted at 173 centers in the United States, Belarus, Poland, Russia and Ukraine.[9] Subjects received ozanimod or comparator (interferon β1a, a product approved for the treatment of relapsing forms of multiple sclerosis) for up to one year (in Trial 1) or up to two years (in Trial 2).[9] Neither the subjects nor the health care providers knew which treatment was being given until the trials were completed.[9] The benefit of ozanimod was evaluated based on the percentage of subjects who experienced reduction in disease relapse in comparison to subjects treated with interferon β1a.[9]

In May 2021, the FDA approved ozanimod for an additional indication for the treatment of moderately to severely active ulcerative colitis.[7]

Clinical trials

Touchstone

Touchstone is a double-blind, placebo controlled phase II clinical for the treatment of ulcerative colitis.[23][24] 197 patients, ages 18–75, with moderate to severe ulcerative colitis (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 ulcerative colitits and total lymphocyte decrease as compared to the placebo, with the most common adverse effects being headaches and anemia.[23] The authors noted that limitations on this study included a brief duration and small sample size, meaning they could not assess safety nor efficacy.[23]

Radiance

Radiance is a double-blind, placebo controlled phase combined II/III clinical trial for the treatment of relapsing multiple sclerosis.[25][26] For the phase II trial, 258 patients, ages 18–55 with relapsing multiple sclerosis (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.[25] Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis over a period of 24 weeks.[25] 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.[25][citation needed] 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.[25] 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.[25][26]

Sunbeam

Sunbeam is the second relapsing multiple sclerosis phase III clinical trial to establish the dose with optimum safety-benefit relationship, with an estimated size of 1200 patients.[25][27] It began in November 2014, and has an estimated completion date of February 2017.[27][needs update]

Society and culture

Commercial

After going public in May 2013, Receptos, Inc. stock surged with the clinical data ozanimod displayed as a S1P immunomodulating drug.[17][28] In August 2015, Receptos was acquired by Celgene for $7.2 billion through a combination of cash in hand and new debt,[29][19] leading to a one-day 22% increase in Celgene stock value.[citation needed]

Receptos-Celgene patented the synthesis of ozanimod in July 2016.[citation needed][30] 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;[31][28] however, in a "surprise development", the FDA rejected Celgene's initial application for the drug's approval in February 2018.[32][20][33] Celgene refiled in March 2019.[33]

The new owner of the product, Bristol Myers Squibb, received FDA approval for ozanimod (Zeposia) oral capsules on March 26, 2020, for the following adult indications: relapsing forms of multiple sclerosis, including relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis, and clinically isolated syndrome.[8] Ozanimod was approved for medical use[clarification needed] in the European Union in May 2020,[4] and in Australia in July 2020.[1]

Research

Ozanimod is in development for additional immune-inflammatory indications, including Crohn's disease.[34]

References

  1. ↑ 1.0 1.1 1.2 1.3 "Zeposia Australian Prescription Medicine Decision Summary". July 27, 2020. https://www.tga.gov.au/apm-summary/zeposia. 
  2. ↑ "Summary Basis of Decision (SBD) for Zeposia". October 23, 2014. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00508&lang=en. 
  3. ↑ 3.0 3.1 3.2 3.3 "Zeposia- ozanimod hydrochloride capsule Zeposia 7-Day Starter Pack- ozanimod hydrochloride kit Zeposia Starter Kit- ozanimod hydrochloride kit". November 16, 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93ce2fab-edfb-4804-8074-963071de51e4. 
  4. ↑ 4.0 4.1 4.2 4.3 "Zeposia EPAR". March 26, 2020. https://www.ema.europa.eu/en/medicines/human/EPAR/zeposia. 
  5. ↑ "Zeposia Product information". https://ec.europa.eu/health/documents/community-register/html/h1442.htm. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 "Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity". British Journal of Pharmacology 173 (11): 1778–92. June 2016. doi:10.1111/bph.13476. PMID 26990079. 
  7. ↑ 7.0 7.1 "U.S. Food and Drug Administration Approves Bristol Myers Squibb's Zeposia (ozanimod), an Oral Treatment for Adults with Moderately to Severely Active Ulcerative Colitis". Bristol Myers Squibb (Press release). May 27, 2021. Retrieved June 4, 2021.
  8. ↑ 8.0 8.1 8.2 "U.S. Food and Drug Administration Approves Bristol Myers Squibb's Zeposia (ozanimod), a New Oral Treatment for Relapsing Forms of Multiple Sclerosis". Bristol-Myers Squibb Company (Press release). March 26, 2020. Retrieved March 26, 2020.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "Drug Trials Snapshots: Zeposia". March 25, 2020. http://www.fda.gov/drugs/development-approval-process-drugs/drug-trials-snapshots-zeposia.  This article incorporates text from this source, which is in the public domain.
  10. ↑ "Drug Approval Package: Zeposia". April 23, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/209899Orig1s000TOC.cfm. 
  11. ↑ 11.0 11.1 Australian Public Assessment Report: Ozanimod hydrochloride (Report). November 25, 2020. https://www.tga.gov.au/sites/default/files/auspar-ozanimod-hydrochloride-201125.pdf. 
  12. ↑ Publications that refer to fingolimod (Gilenya) also refer to it by its discovery number, which was FTY720. See, for instance, Scott, et al. (2016).
  13. ↑ Per Scott, et al. (2016), "The potency and selectivity of RPC1063 for the S1P receptor family was assessed through inhibition of forskolin‐induced cAMP production (S1P1 receptor), [35S]‐GTPγS binding assays (S1P1,2,3,5 receptors), or β‐arrestin signalling (S1P4 receptor)." Ed. note, for simplicity, receptor subtype subscripts in the quote were altered to match the style of this article.
  14. ↑ Siponimod appears in discovery publications as BAF312, see Scott, et al. (2016). Mocravimod appears in discovery publications as KRP203, see Pérez-Jeldres T; Alvarez-Lobos M & Rivera-Nieves J (June 2021). "Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis". Drugs 81 (9): 985–1002. doi:10.1007/s40265-021-01528-8. PMID 33983615. "Erratum in: Drugs. 2021 Aug;81(12):1451". 
  15. ↑ "S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate". Chemistry & Biology 12 (6): 703–15. June 2005. doi:10.1016/j.chembiol.2005.04.019. PMID 15975516. 
  16. ↑ 16.0 16.1 16.2 16.3 "Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators". Expert Opinion on Drug Metabolism & Toxicology 12 (8): 879–95. August 2016. doi:10.1080/17425255.2016.1196188. PMID 27249325. 
  17. ↑ 17.0 17.1 17.2 Pollack, Andrew (July 14, 2015). "Celgene Agrees to $7.2 Billion Deal for Receptos". The New York Times (NYTimes.com). https://www.nytimes.com/2015/07/15/business/dealbook/celgene-agrees-to-7-2-billion-deal-for-receptos.html. "The biotechnology company Celgene agreed on Tuesday to pay $7.2 billion in cash to acquire Receptos, which is developing a potentially promising drug for autoimmune diseases. ... Receptos, based in San Diego, is developing a drug called ozanimod that is now in late-stage clinical trials as a treatment for multiple sclerosis and ulcerative colitis, with an approval possible for multiple sclerosis as early as 2018 and for ulcerative colitis the year after. / ... / Receptos was formed in 2009 with patents licensed from the Scripps Research Institute. ... ozanimod... was previously called RPC1063. / ... / Ozanimod has the same mechanism of action as Gilenya, a successful multiple sclerosis drug sold by Novartis. But Celgene executives say ozanimod could be safer than Gilenya, which has cardiac side effects." 
  18. ↑ 18.0 18.1 "FDA approves ozanimod, a drug invented at Scripps Research, for treatment of multiple sclerosis". Scripps.edu (Press release). Retrieved December 5, 2020. Hugh Rosen, MD, PhD... invented ozanimod along with fellow Scripps Research professor Edward Roberts, PhD, and their laboratory colleagues. / ... / The fundamental discoveries that led to ozanimod were reported by Rosen, Roberts and their Scripps Research colleagues in a series of papers from 2002 to 2008. In 2009, Scripps Research licensed ozanimod to biotechnology startup Receptos, which Celgene purchased in 2015 for $7.3 billion. Celgene was acquired by Bristol Myers Squibb in 2019.
  19. ↑ 19.0 19.1 19.2 "Celgene to Acquire Receptos, Advancing Leadership in Immune-Inflammatory Diseases". Celgene Corporation (Press release). July 14, 2015. Archived from the original on June 4, 2021. Retrieved June 4, 2021. Patents supporting Ozanimod were exclusively licensed to Receptos from The Scripps Research Institute (TSRI).
  20. ↑ 20.0 20.1 Taylor, Nick Paul (June 13, 2018). "Biotech: Celgene executive blames Receptos for ozanimod filing fail". Fierce Pharma (Framingham, Mass.: Questex). https://www.fiercebiotech.com/biotech/celgene-exec-blames-receptos-for-ozanimod-filing-fail. "Nadim Ahmed said Celgene’s arm’s-length relationship with the biotech it bought for $7.2 billion three years ago led to a substandard filing and embarrassing refusal-to-file notice. / The FDA hit Celgene with the notice in February after a readthrough of the filing revealed the firm had failed to provide the necessary preclinical and clinical pharmacology information on the multiple sclerosis drug. That delayed approval of a key pipeline prospect with forecast peak sales of around $5 billion a year." 
  21. ↑ Liu, Angus (January 6, 2020). "The Top 10 Largest Biopharma M&A Deals in 2019 [1. Bristol-Myers Squibb/Celgene"]. Fierce Pharma. Framingham, Mass.: Questex. p. 2. https://www.fiercepharma.com/special-report/1-bristol-myers-squibb-celgene. "On Nov. 20, Bristol-Myers closed the takeover, officially putting an end to Celgene's 34-year run. Along the way, the legacy Celgene portfolio has turned up some positive news. / ...applications for ozanimod in relapsing forms of MS have been accepted by regulators in both the U.S. and Europe, setting up potential approvals next year." 
  22. ↑ "Bristol-Myers Squibb Completes Acquisition of Celgene, Creating a Leading Biopharma Company". Bristol Myers Squibb (Press release). April 12, 2019. Retrieved June 4, 2021.
  23. ↑ 23.0 23.1 23.2 "Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis". The New England Journal of Medicine 374 (18): 1754–62. May 2016. doi:10.1056/NEJMoa1513248. PMID 27144850. 
  24. ↑ Efficacy and Safety Study of Ozanimod in Ulcerative Colitis. July 23, 2012. https://clinicaltrials.gov/ct2/show/NCT01647516. Retrieved June 4, 2021. 
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 "Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial". The Lancet. Neurology 15 (4): 373–81. April 2016. doi:10.1016/s1474-4422(16)00018-1. PMID 26879276. 
  26. ↑ 26.0 26.1 Clinical trial number NCT01628393 for "Efficacy and Safety Study of RPC1063 in Relapsing Multiple Sclerosis Patients (Radiance Study)" at ClinicalTrials.gov
  27. ↑ 27.0 27.1 Study of Ozanimod (RPC1063) in Relapsing Multiple Sclerosis (MS). November 19, 2014. https://clinicaltrials.gov/ct2/show/NCT02294058. Retrieved June 4, 2021. 
  28. ↑ 28.0 28.1 "Celgene 2015 Annual Report". http://files.shareholder.com/downloads/AMDA-262QUJ/3100938083x0x889847/98954B20-BFA0-4AD4-9649-105595A19800/Celgene_2015_Annual_Report.pdf. 
  29. ↑ Rockoff, Jonathan D. (July 14, 2015). "Celgene to Buy Receptos for $7.2 Billion". The Wall Street Journal (WSJ.com). https://www.wsj.com/articles/celgene-to-buy-receptos-for-about-7-2-billion-1436908831. "Cancer-drug company Celgene Corp. on Tuesday said it will pay $7.2 billion for Receptos Inc. in a bid to move deeper into the multibillion-dollar market for autoimmune diseases." 
  30. ↑ Yeager AR, Brahmachary E, Martinborough E, Scott FL, Timony GA, Brooks JL, Tamiya J, Huang L, Moorjani M, Boehm MF, Hanson MA, Peach R, "Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis", US patent 9388147, published October 22, 2015, assigned to Receptosand Celgene International II Sarl
  31. ↑ GE&BN Staff (July 14, 2015). "Celgene to Acquire Receptos for $7.2B". Genetic Engineering & Biotechnology News (GE&BN, GenEngNews.com). Larchmont, N.Y.: Mary Ann Liebert, Inc.. http://www.genengnews.com/gen-news-highlights/celgene-to-acquire-receptos-for-7-2b/81251504. "Celgene has agreed to acquire Receptos for about $7.2 billion, in a deal intended to enhance the buyer’s inflammation and immunology (I&I) portfolio, the companies said today. / The deal will add to Celgene’s pipeline the Phase III compound Ozanimod, an oral, once-daily, selective sphingosine 1-phosphate 1 and 5 receptor modulator (S1P). / Ozanimod is expected to generate annual sales ranging from $4 billion to $6 billion—and expand an I&I franchise whose projected 2020 net product sales Celgene said are expected now to exceed $4 billion, up from the previous target of $3 billion... / Ozanimod is the subject of Phase III trials that include TRUE NORTH in ulcerative colitis (UC)... expected to generate data in 2018; and two trials in relapsing multiple sclerosis (RMS), RADIANCE and SUNBEAM... randomized, controlled, double-blind studies designed to compare... Ozanimod against interferon beta-1a (Avonex®) in patients with RMS." 
  32. ↑ "U.S. FDA Rejects Filing for Celgene MS Drug, Shares Fall". Reuters.com. https://www.reuters.com/article/us-celgene-fda/u-s-fda-rejects-filing-for-celgene-ms-drug-shares-fall-idUSKCN1GB30U. "U.S. health regulators have rejected Celgene Corp’s application seeking approval of a key multiple sclerosis drug due to insufficient data, the company said on Tuesday, a surprise development that will likely delay the entry to market of one of Celgene’s most important pipeline assets. / Celgene shares fell nearly 8 percent after it revealed that it had received a “refusal to file” letter from the ... FDA.. for its ozanimod for the treatment of patients with relapsing multiple sclerosis. / ...it expected U.S. approval of ozanimod by the end of this year and planned to file for European approval during the current quarter. The timeline for a U.S. approval decision is now far less certain. / ... / Upon preliminary review, the FDA determined that the nonclinical and clinical pharmacology sections in the new drug application are insufficient to permit a complete review, the company said." 
  33. ↑ 33.0 33.1 Staines, Richard (March 27, 2019). "Celgene Refiles Potential MS Blockbuster Ozanimod with FDA". Pharmaphorum.com. West Byfleet, Surrey, England: Pharmaphorum Media Limited. https://pharmaphorum.com/news/celgene-refiles-potential-ms-blockbuster-ozanimod-with-fda/. "Celgene has filed its highly anticipated oral MS drug ozanimod with the US regulator, more than a year after the FDA rejected it... / Last February Celgene received a “Refuse to File” notice from the FDA after finding issues with the dossier submitted by the company’s Receptos unit, which first developed the drug. / ... / Without Celgene overseeing the dossier... Receptos had failed to provide the necessary preclinical and clinical pharmacology information on the MS drug. / Celgene will be hoping the issues are in the past with its new filing for ozanimod in relapsing forms of [MS], which is tipped for annual sales in the region of $5 billion, although a newly-approved... Novartis’ rival pill Mayzent (siponimod) could make this much harder to achieve. / Ozanimod will be particularly important... should the $74 billion merger with Bristol-Myers Squibb go ahead next month." 
  34. ↑ "Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study". The Lancet. Gastroenterology & Hepatology 5 (9): 819–828. September 2020. doi:10.1016/S2468-1253(20)30188-6. PMID 32553149. 

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