Ozanimod

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Ozanimod
Ozanimod.svg
Ozanimod ball-and-stick model.png
Clinical data
Synonyms RPC1063
ATC code
  • None
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Elimination half-life 19 hours
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C23H24N4O3
Molar mass 404.46 g/mol
3D model (JSmol)

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]

Pharmacology[edit]

Pharmacodynamics[edit]

Ozanimod 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]

Pharmacokinetics[edit]

Ozanimod 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 trials[edit]

Touchstone[edit]

Touchstone is a double-blind, placebo controlled phase II clinical for the treatment of ulcerative colitis. (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]

Radiance[edit]

Radiance is a double-blind, placebo controlled phase combined II/III clinical trial for the treatment of relapsing multiple sclerosis (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]

Sunbeam[edit]

Sunbeam is the second RMS phase III clinical trial to establish the dose with optimum safety-benefit relationship, with an estimated size of 1200 patients (NCT02294058).[7][10] It began in November 2014 and has an estimated completion date of February 2017.[10]

Commercial[edit]

After 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]

References[edit]

  1. ^ a b c d e f g h Scott, F L; Clemons, B; Brooks, J; Brahmachary, E; Powell, R; Dedman, H; Desale, H G; Timony, G A; Martinborough, E (2016-06-01). "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): 1778–1792. doi:10.1111/bph.13476. ISSN 1476-5381. PMC 4867749Freely accessible. PMID 26990079. 
  2. ^ a b "Celgene Press Release". 
  3. ^ Jo, E. (2005). "S1P1-selective in vivo-active agonists from high- throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate". Chemical Biology. 12 (6): 703–715. doi:10.1016/j.chembiol.2005.04.019. 
  4. ^ a b c d Juif, P-E. (2016). "Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators". Expert Opinion on Drug Metabolism & Toxicology. 5255 (8): 879. doi:10.1080/17425255.2016.1196188. 
  5. ^ a b c Sandborn, W. (2016). "Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis". New England Journal of Medicine. 374 (18): 1754–62. doi:10.1056/NEJMoa1513248. PMID 27144850. 
  6. ^ "Efficacy and Safety Study of RPC1063 in Ulcerative Colitis". ClinicalTrials.gov. 
  7. ^ a b c d e f g Cohen, Jeffrey A; Arnold, Douglas L; Comi, Giancarlo; Bar-Or, Amit; Gujrathi, Sheila; Hartung, Jeffrey P; Cravets, Matt; Olson, Allan; Frohna, Paul A (2016). "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): 373–381. doi:10.1016/s1474-4422(16)00018-1. 
  8. ^ a b "Efficacy and Safety Study of RPC1063 in Relapsing Multiple Sclerosis Patients (Radiance Study) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. 
  9. ^ Hartung, J. (2012). "Results of a Thorough QT/QTc (TQT) Study of Orally Administered RPC1063, a Novel, Selective S1P1 Receptor Agonist, in Healthy Adult Volunteers" (PDF). 
  10. ^ a b "Phase 3 Study of RPC1063 in Relapsing MS - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-11-09. 
  11. ^ "Celgene Agrees to $7.2 Billion Deal for Receptos". New York Times. 
  12. ^ a b "Celgene 2015 Annual Report" (PDF). 
  13. ^ "Celgene to Buy Receptos for $7.2 Billion". Wall Street Journal. July 14, 2015. 
  14. ^ "SELECTIVE SPHINGOSINE 1 PHOSPHATE RECEPTOR MODULATORS AND METHODS OF CHIRAL SYNTHESIS". U.S. Patent & Trademark Office. July 12, 2016. 
  15. ^ "Celgene to Acquire Receptos for $7.2B". Genetic Engineering & Biotechnology News. 
  16. ^ Editorial, Reuters. "U.S. FDA rejects filing for Celgene MS drug, shares fall". U.S. Retrieved 2018-03-28.