Ozanimod, sold under the brand name Zeposia, is an
immunomodulatory medication for the treatment of relapsing
multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
and
ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...
.
It acts as a
sphingosine-1-phosphate
Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcoho ...
(S1P)
receptor agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an ...
, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.
The most common adverse reactions are upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.
Ozanimod was approved for medical use in the United States in March 2020,
[ ] in the European Union in May 2020,
and in Australia in July 2020.
Medical uses
In the United States, ozanimod is
indicated
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
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.
In the European Union and in Australia, ozanimod is indicated for the treatment of adults with relapsing remitting multiple sclerosis.
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
Fingolimod, sold under the brand name Gilenya, is an immunomodulating medication, mostly used for treating multiple sclerosis (MS). Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preven ...
(trade name Gilenya), a non‐selective S1P modulator.
The prospects for ozanimod (Scripps-Receptos compound RPC1063) depended upon demonstration of comparable or better activity and selectivity relative to fingolimod and other comparators. During the discovery phase of its development, ozanimod was shown to be a selective agonist of the S1P1 and S1P5 receptors.
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.
Potency for ozanimod as an agonist of the S1P1 receptor type was established through observed sub-
nanomolar
Molar concentration (also called molarity, amount concentration or substance concentration) is a measure of the concentration of a chemical species, in particular of a solute in a solution, in terms of amount of substance per unit volume of solut ...
EC
50 values in GTPγS binding and cAMP inhibition assays, and for the S1P5 type through an observed nanomolar EC
50 value in the GTPγS binding assay.
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.
Also, these assays allowed comparison of ozanimod potency against and selectivity for S1P1 over other S1 receptors, relative to related S1 active agents
siponimod
Siponimod, sold under the brand name Mayzent, is a selective sphingosine-1-phosphate receptor modulator for oral use that is used for multiple sclerosis (MS). It is intended for once-daily oral administration.
In March 2019, it was approved in ...
and the phosphorylated (
prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
) forms of
fingolimod
Fingolimod, sold under the brand name Gilenya, is an immunomodulating medication, mostly used for treating multiple sclerosis (MS). Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preven ...
and
mocravimod, where ozanimod was similar to these comparators in S1P1 potency, but had the elevated selectivities stated above (versus
fingolimod
Fingolimod, sold under the brand name Gilenya, is an immunomodulating medication, mostly used for treating multiple sclerosis (MS). Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preven ...
being potent in stimulating S1P3, S1P4, and S1P5,
siponimod
Siponimod, sold under the brand name Mayzent, is a selective sphingosine-1-phosphate receptor modulator for oral use that is used for multiple sclerosis (MS). It is intended for once-daily oral administration.
In March 2019, it was approved in ...
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.
Hence, the study concluded that it had "established... RPC1063
sa 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".
Pharmacodynamics and pharmacokinetics
The agonism of S1P directly causes its internalization and degradation through the
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
-proteosome pathway.
The loss of S1P leads to a decrease in the total lymphocyte count in circulation, specifically
CD4+
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...
CCR7+ and
CD8+
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
CCR7+ T cells.
Ozanimod has a high oral bioavailability, a circulating half-life of about 19 hours, and reaches highest blood plasma concentrations after about 6 hours.
Ozanimod is dehydrogenated by two CYP enzymes into two active metabolites, all with similar pharmacokinetics.
The decrease in lymphocyte count lasts for approximately 14 days after treatment discontinuation.
Unlike fingolimod, it does not require phosphorylation for activation, nor does it demonstrate cardiac abnormalities or hepatotoxicity.
History
Ozanimod was invented by
Hugh Rosen,
Edward Roberts, and colleagues at
The Scripps Research Institute
Scripps Research, previously known as The Scripps Research Institute (TSRI), is a nonprofit American medical research facility that focuses on research and education in the biomedical sciences. Headquartered in San Diego, California, the institu ...
, and was subsequently out-licensed in the creation of the
startup, Receptos Inc.
Celgene Corp acquired Receptos along with its
intellectual property
Intellectual property (IP) is a category of property that includes intangible creations of the human intellect. There are many types of intellectual property, and some countries recognize more than others. The best-known types are patents, cop ...
in 2015.
Bristol Myers Squibb
The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...
acquired Celgene in 2019 (and with it, ozanimod and the rest of its products and pipeline).[
The US ]Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(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. The trials were conducted at 173 centers in the United States, Belarus, Poland, Russia and Ukraine. 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). Neither the subjects nor the health care providers knew which treatment was being given until the trials were completed. 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.
In May 2021, the FDA approved ozanimod for an additional indication for the treatment of moderately to severely active ulcerative colitis.
Clinical trials
Touchstone
Touchstone is a double-blind, placebo controlled phase II clinical for the treatment of ulcerative colitis. 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. The authors noted that limitations on this study included a brief duration and small sample size, meaning they could not assess safety nor efficacy.
Radiance
Radiance is a double-blind, placebo controlled phase combined II/III clinical trial for the treatment of relapsing multiple sclerosis. 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. Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis over a period of 24 weeks. 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. 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. 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.
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. It began in November 2014, and has an estimated completion date of February 2017.
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. 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 one-day 22% increase in Celgene stock value.
Receptos-Celgene patented the synthesis of ozanimod in July 2016. 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, in a "surprise development", the FDA rejected Celgene's initial application for the drug's approval in February 2018. Celgene refiled in March 2019.[
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.] Ozanimod was approved for medical use in the European Union in May 2020, and in Australia in July 2020.
Research
Ozanimod is in development for additional immune-inflammatory indications, including Crohn's disease.
References
External links
*
*
*
*
{{Portal bar , Medicine
1-Aminoindanes
Bristol Myers Squibb
Ethanolamines
Immunomodulating drugs
Isopropyl compounds
Nitriles
Noninfective enteritis and colitis
Oxadiazoles
Phenol ethers