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Chemistry and Pharmacology of Drug Discovery
pain, impaired mobility, cognitive problems that often interfere with personal
5
relationships, and impact quality of life (QOL).
Over the last decade, the prevalence of
MS has been increasing worldwide and ranges from 5 to 300 per 100,000 people.
Relapsing-remitting multiple sclerosis (RRMS) is the most common type of MS,
marked by discrete, day-to-week attacks (relapses), followed by a week-to-month
symptom-free interval (remissions). Approximately 85% of people with MS are initially
diagnosed with RRMS. The exact etiology and pathogenesis of MS are still uncertain, but
it is commonly believed that both genetic and environmental factors contribute to the
aberrant immune responses leading to disease progression. Currently there’s no cure for
MS patients and the most common treatment has evolved from immunosuppressant in
mid-1990s to disease-modifying therapies (DMTs) today. The first disease-modifying
drug for RRMS, interferon beta-1 (IFNβ-1) was the key breakthrough for the treatment of
6,7
It can dramatically reduce the number of attacks and disease progression in the
MS.
early relapsing phases of MS, but not in the advanced phases.
8
Inflammatory bowel diseases (IBDs) are chronic relapsing inflammatory
disorders of the gastrointestinal tract characterized by two major clinically defined forms:
ulcerative colitis (UC) and Crohn’s disease (CD). Like MS, the etiology of IBD is not
fully understood with immunologic abnormalities, genetics, environmental factors, and
2,9
the microbiota all playing a role.
UC involves localized superficial inflammation that
affects the colon and only invades the inner lining of bowel tissue. CD manifests as
transmural inflammation that can spread anywhere in the gastrointestinal (GI) tract and
2,10
penetrates the intestinal layers from inner to outer lining.
IBD is high, with approximately 4.9 million cases in 2019.
for UC include aminosalicylates, corticosteroids, and thiopurines.
The global prevalence of
11,12
Conventional treatments
8
In the late 1990s, the
advent of anti-tumor necrosis factors (TNFs) made a major impact on the therapeutic
13
algorithms and until now they remain the frontline treatment of IBD.
However, many
patients still require alternative therapies due to non-response, loss of response, or
13
intolerance of anti-TNFs.
At first glance, MS and IBD are clinically distinct diseases. However, for
decades, mounting evidence have prompted researchers to suspect about a possible link
14–16
between the two.
Both MS and IBD are diseases of a relapsing and remitting nature
and are mediated by the impairment of the immune system; they are also prevalent in
17
young people in the developed countries.
Many patients with IBD (particularly UC)
exhibit abnormal T2 signals in the white matter, accompanied or not by clinical
18,19
symptoms that mimic MS.
patients with MS compared to the general population.
Other research indicates an increased risk of IBD among
20,21
A systematic review showed a
50% increased risk of comorbidities between IBD and MS without any significant
22
difference for this association between the UC and CD.
Besides the evidence that commensal gut bacteria play a role in both IBD and
scientists have revealed that bidirectional communication of inflammatory signals
MS,
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Chapter 11. Ozanimod (Zeposia)
through the gut-brain axis is important to relay the health status of the host and stimulate
23,24
regulatory responses.
The migration of intestinal immune cells to CNS may
contribute to the pathogeneses of neurological and neurovegetative diseases such as
24
MS.
More recent studies at molecular level have demonstrated in both MS and IBD,
Th17 cell play important roles. Th17 cells promote inflammation primarily through the
25,26
secretion of cytokines such as IL-17 and TNF-α.
Either alone or in conjunction with
TNF-α, IL-17 promote the secretion of inflammatory mediators, chemokines and
proteases. These factors induce inflammation and promote the enlisting, activation and
movement of neutrophil to target tissues.
27,28
In addition, evidence has shown that in both
MS and IBD, the overproduction of TNF contributes to various pathological hallmarks
13,25,26
such as demyelination and transmural inflammation.
The mysterious relationship between IBD and MS continues when taking the
therapies into picture. If TNF overproduction plays an important role in both IBD and
MS, then why anti-TNF drugs such as Infliximab and Adalimumab can significantly
increase MS incidence in IBD patients?
that worked miracle in some MS patients, was reported to exacerbate IBD symptoms?
29,30
To add to the riddle, why INF-β therapies,
31
Considering the common immunological and pathophysiological overlaps between IBD
and MS, the discrepancies in their responses to the same treatment suggest additional
mechanism might exist that scientists yet to find out.
1.2. Treatment That “Kills Two Birds with One Stone”
Natalizumab is one of the successful treatments for both MS and CD developed around
2000s. As a humanized monoclonal IgG4κ antibody, Natalizumab can selectively bind to
α4-integrin and inhibit the interaction of α4β1 with VCAM-1 and α4β7 with MAdCAM-
32
1.
Both VCAM-1 and MAdCAM-1 are found on endothelial cells and interact with
α4β1 and α4β7 on leukocytes for firm adherence before extravasation into inflamed
33
tissues.
blood vessels into target organs.
As a result, natalizumab prevents migration of autoreactive leukocytes out of
34
Despite its success, evidence has emerged to show that
some integrins such as α4β1, αLβ2, also play important roles in other immune
phenomena such as the formation of immune synapse and the differentiation of Th1
lymphocytes. Therefore, long-term administration of blocking agents such as
35
Natalizumab may result in adverse effects.
Fingolimod was discovered in 1995–1996 following a chemical derivatization
36,37
program based on the fungal metabolite myriocin (also known as ISP-1).
Researchers
found the binding of fingolimod to a new molecular target directly located in the lymph
node (LN) and not at the vascular levels that led to the unveiling of the metabolisms
38
behind S1P and its receptors.
Since then, this class of drug known as S1P receptor
modulators has gained great interest and the second-generation compounds such as
ponesimod (ACT-128800), siponimod (BAF312), ceralifimod (ONO-4641), ozanimod
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Chemistry and Pharmacology of Drug Discovery
(1, RPC-1063), and amiselimod (MT-1303) with higher receptor selectivity were
39
developed.
Comparing with anti-integrin therapies, which requires invasive route of
administration, S1PR modulators are orally administered with other inherent advantages
such as low manufacturing cost and the absence of immunogenicity (Figure
1).
Figure 1. The structure of fingolimod
Ozanimod (1) is the first S1P modulator that has the potential to become a
combinatory treatment for both MS and IBD. It was approved by the US Food and Drug
Administration (FDA) for the management of MS in 2020 and UC in 2021. The ongoing
clinical trial YELLOWSTONE (Phase 3) is designed to test the safety and efficacy of
40
ozanimod (1) in patients with CD.
Ozanimod (1) is also the first drug tested in human subjects after the
establishment of the Molecular Libraries Program (MLP) funded by National Institute of
Health (NIH).
41
The initial discovery of ozanimod (1, RPC-1063) was reported by Rosen,
Roberts and their teams at Scripps Research Institute in a series of papers from 2002 to
42–45
2008.
In 2009, Scripps Research licensed ozanimod (1) to a biotechnology start-up
Receptos while MLP undertook the assay development, high-throughput screening (HTS)
46
and medicinal chemistry.
began its phase 1 study.
Within 18 months, the company optimized ozanimod (1)
47
Receptos was subsequently purchased by Celgene in 2015 for
US$ 7.3 billion, which was later acquired by Bristol-Myers Squibb in 2019 (Figure 2).48
2. Pharmacology
2.1. S1P and Its Receptors
Sphingosine-1-phosphate (S1P) is lipid molecule with bioactive properties involved in
numerous cellular processes such as cell growth, movement, programmed cell death, self-
Figure 2. The structure of ozanimod (1)
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Chapter 11. Ozanimod (Zeposia)
degradation, cell specialization, aging, and immune system reactions.49 With sphingoid
bases as building blocks, all cells make S1P intracellularly as an essential element in
38,50
).
membrane structure (Figure 3
Figure 3. The structure of sphingosine-1-phosphate
S1P is also secreted. Extracellular S1P acts as a signaling molecule and is
10,51
involved in many physiological processes.
52
role in supporting T-cell survival.
At sites of inflammation, S1P is involved in the
recruitment of immune cells, which could further exacerbate the inflammatory process.
In immune cells, S1P plays an important
53
It is important to note that S1P signaling can be essential in an inflammatory response
54
regardless of its concentration gradients (more details below).
S1P also holds an
important function in the regulation of vascular integrity as a suppressor of
49
angiogenesis.
Extracellular S1P work as a ligand of high affinity G-protein-coupled receptors
55
(GPCRs) on cell surfaces.
These receptors comprise five distinct subtypes which are
linked to diverse signaling pathways and are regulated by distinct mechanisms. T and B
lymphocytes, as well as endothelial cells, all express distinctive profiles of S1P receptors,
which are major regulators of development, recirculation, tissue homing patterns and
56
chemotactic responses to chemokines of B and T cells.
S1P receptor subtype 1 (S1PR1) is expressed by lymphocytes, dendritic cells,
cardiomyocytes and vascular endothelial cells and is involved in the regulation of chronic
inflammation via mediation of lymphocyte egress from secondary lymphoid organs.
57,58
When S1PR1’s function is blocked, lymphocytes are sequestered in the LNs and
59
thymus.
recruitment and vascular permeability.
role in lymphocyte retention within inflamed tissues.
S1PR1 is also expressed on endothelium where it is involved in dendritic cell
59
During inflammation, S1P-S1PR1 may play a
56
The S1P-S1PR1 axis also
participates in naïve B cell trafficking from bone marrow to blood, egress from secondary
56
lymphoid organs, and marginal B cell localization in spleen.
Stimulating S1PR1 leads
to the activation of G protein and subsequently Ras, phosphatidylinositol 3-kinase
(PI3K), phospholipase C (PLC), signal transducers, activators of transcription 3
(STAT3), and nuclear factor kappa B (NF-κB). RAS and PI3K, in return, activate
60–62
extracellular regulated protein kinase (ERK), Rac and protein kinase B (Akt).
All
these events result in T cells egress from LNs, negative inotropy, cardio-protection and
63
endothelial function.
pro-inflammatory role.
S1PR2 receptors might have opposite functions to S1PR1 with a
56
It is also involved in mast cell degranulation, histamine
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secretion, bronchial smooth muscle contraction and hair cell survival in the inner ear.
Chemistry and Pharmacology of Drug Discovery
64
Together with S1PR1, S1PR3 is important in the regulation of heart rate in human.65 In
addition, S1PR3 modulation was found linking to heart rate effects and the risk for type I
and II atrioventricular block.
also on airway smooth muscle cells, which regulates cytokine production by T cells.
66
S1PR4 is expressed predominantly on immune cells but
67
S1PR4 stimulation contributes to the activation of dendritic cells.68 S1PR5 is expressed
primarily in CNS white matter tracts, predominantly by oligodendrocytes, the survival of
69
which is promoted by S1P activation.
cell development and trafficking from bone marrow.
In addition, S1PR5 also regulates natural killer
59
S1PR1, S1PR2, and S1PR3 are
broadly expressed in most of organs, while S1PR4 and S1PR5 are primarily expressed in
70
lymphoid tissues and the lung and brain, leukocytes and spleen respectively.
Currently, there are four S1PR modulators: fingolimod, siponimod, ozanimod
(1), and ponesimod that obtained regulatory approvals. Fingolimod (FTY720) is a
prodrug that requires phosphorylation into their bioactive form whereas others are direct
acting. As a first generation S1P receptor modulator, fingolimod targets four of the five
receptors (S1PR1, 3, 4, and 5) and Phosphorylated FTY720 (pFTY720) binds both
42,71
S1PR1 and S1PR5 with high affinity.
In the case of S1PR1, FTY720 has mixed
agonist–antagonist effects, where it initially induces strong activation of the receptor and
72
likely causes the acute cardiac side effects in patients.
However, pFTY720 also shifts
S1PR1 into a conformation that results in preferential ubiquitination and degradation, and
73
S1PR1 is ultimately lost from the cell surface after FTY720 treatment.
For immune cell
trafficking, it is not essential to resolve whether FTY720 acts primarily as an agonist or
antagonist, as the cells would not follow S1P gradients because it is seeing an S1P
receptor signal either everywhere (if FTY 720 is an agonist) or nowhere (if FTY720 is an
54
antagonist).
targeting S1P signaling have entered clinical trials.
Following the success of FTY720, at least a dozen additional drugs
74
Siponimod and ozanimod (1) are
S1PR1 and S1PR5 modulators, while Ponesimod is specific for S1PR1.
2.2. S1P Concentration Gradient and Lymphocytes
Egress
Through a series of balanced enzymatic pathways, synthetic and degradative enzymes are
responsible for the synthesis of S1P and the maintenance of its concentration in various
tissue types. S1P is generated intracellularly through phosphorylation of sphingosine by
sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) and can be reversibly
dephosphorylated to sphingosine by sphingosine phosphatases 1, 2 and irreversibly
degraded by S1P lase.
interstitial spaces including immune organs such as spleen, thymus and LNs. This
differential in S1P concentrations across various tissue types is known as the S1P
75
S1P concentration is much higher in blood and lymph than
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Chapter 11. Ozanimod (Zeposia)
gradient and plays a key role in the trafficking of lymphocytes and other leukocytes from
76
immune organs to sites of inflammation.
There are many theories on how S1P gradients
are created and maintained, and many reviews have in depth discussions regarding this
process.
77–80
S1PR1 on lymphocytes is very sensitive to S1P exposure and gets completely
internalized after incubation with as little as 1nM S1P for 20 min ex vivo. The high
concentration of S1P (~1 μM) in blood guides immune cells out of the thymus, spleen,
and bone marrow.
internalize their surface S1PR1.
from blood inefficiently, presumably because they do not lose their attraction to blood.
Plasma S1P turns over rapidly with a half-life of only 15 mins.
81
In response to the abundant blood S1P, T cells in blood fully
82
If S1PR1 internalization is blocked, T cells enter LNs
54,83
82
Lymph S1P is supplied by lymphatic endothelial cells with a high concentration
of ~0.1 μM.
81
Immune cells are guided out of LNs, Peyer patches, and nonlymphoid
tissues by lymph S1P and then travels into circulation. Plasma S1P entering tissues are
destroyed to maintain the S1P gradients between tissues and circulation, but it remains a
54
mystery how it is achieved.
S1P signaling plays a critical role in mature T-cell exit from the thymus and a
54
supporting role in immune cell exit from the bone marrow.
The S1P gradient between
the thymic parenchyma and blood is tightly controlled and T-cell exit is very sensitive to
54
disruption of the gradient.
corticomedullary junction.
abundant S1PR1 to navigate selection and leave.
T cells leave the thymus via specialized vessels at the
84
The process ensures only mature T cells that express
54
Comparing with the exit from the
thymus into blood, exit from bone marrow into blood is only weekly dependent on S1P
gradients.
54
It was found that loss of any of the receptors known to mediate exit from
bone marrow (S1P receptors, CCR2 for monocytes, or CXCR2 for neutrophils), leads to a
much less profound block in bone marrow exit than loss of S1PR1 for thymic exit.
85
It is
possible that the highly porous bone marrow endothelium, which permits passive export
of red blood cells, can permit passive export of white blood cells in the absence of strong
85
retention signals.
Lymphocytes exit from the spleen has been more difficult to study
than those exiting from LNs, because both entry and exit are via blood. However strong
evidence suggests that splenic egress is driven by S1P gradients between spleen and
54
blood.
Follicular B cell exit from the spleen into blood in an S1PR1-dependent manner
that has been confirmed by intravital two photon microscopy: S1PR1-deficient B cells
exited the B follicle into the marginal zone at a rate at least 10-fold lower than that of
86
wild-type B cells.
Mature lymphocytes circulate among secondary lymphoid organs including
51
LNs, spleen, and Peyer patches.
Lymphocytes from blood enter LNs and mucosa
associated lymphoid tissues via high endothelial venules (HEVs) located in the T cell
54
zones.
When a naïve T cell enters a lymphoid node where S1P concentration is low, it
gradually recovers the surface expression of S1PR1 and regains the ability to migrate out
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from lymphoid nodes toward the higher S1P concentrations in blood and lymph.
Chemistry and Pharmacology of Drug Discovery
87,88
This
re-expression takes several hours (~4–24 h), which allows a naïve T cell to interact with
antigen-presenting cells.
89
If a naïve T cell is activated by antigen in the lymph node, the
re-expression of S1PR1 is then suppressed for several days through antigenic stimulation
and interferon binding, which renders the antigen-activated T cells transiently insensitive
89
to the S1P gradients.
After several days of clonal expansion and differentiation into
effector cells, S1PR1 is re-expressed which makes the cells responsive to S1P
89
concentration and exit the lymph node.
In most cases, activated lymphocytes exit LNs
to travel to sites of infection. However, LNs egress also enables tissue damage in
54
autoimmune diseases and in some cases, also contributes to disease dissemination.
In the case where a naïve T cell is not activated by antigen in the lymph node,
the cells re-express S1PR1 after several hours, exit lymph nodes and eventually return to
89
the blood stream which completes one circulation loop.
Thus, lymphocytes utilize this
S1P gradient between lymphoid organs and the circulation as a cue for the egress process.
Disruption of the S1P gradient either by inhibition of sphingosine kinase or by inhibition
87
of S1P lyase results in lymphopenia due to defect in the lymphocyte egress.
In addition,
S1P production is also triggered by the pro-inflammatory cytokines such as interleukin-1
(IL-1), TNF-α, and vascular endothelial growth factor (VEGF), increasing S1P
90
concentration in efferent lymphatic vessels.
This increase of the S1P gradient between
the LNs and the efferent lymphatic vessel during inflammation causes lymphocytes to
exit the LNs, re-enter blood stream, be mobilized to the site of inflammation and
91
perpetuate the inflammatory response.
The function of S1P receptors to guide immune cells from the low S1P
environment of the LNs to the high S1P environment of the lymph has triggered intense
research activities. However, one should understand it can be extremely challenging to
measure extracellular signaling-available S1P in LNs. As S1P is a lipid, there is no
54
mRNA to track, and there is also no single protein can serve as a proxy.
many data to test the S1P signaling can be more elusive than one might expect.
Therefore,
54
In
addition, S1P signaling contributes to multiple aspects of an immune response and it has
been difficult to construct a holistic picture of how S1P signaling affect diseases.
Therefore, it seems likely that the efficacy of S1P modulating drugs is attributable to
multiple processes.
2.3. Ozanimod Mechanism of Action
In vitro studies suggested ozanimod (1) showed its greatest affinity for S1PR1 and
S1PR5 specifically. Its affinity for S1PR1 was found to be 27-times greater than for
S1PR5 and greater than 10,000-fold over S1PR2,3,4.
mechanisms of action for ozanimod (1).
10
There are several proposed
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Chapter 11. Ozanimod (Zeposia)
It is proposed that the primary mechanism of action for ozanimod (1) is its
effects as an S1PR modulator on the trafficking of immune cells. And the model of
“functional antagonism” as a mode of action for S1PR1 agonists such as ozanimod (1) is
92
now well established.
exerts an agonistic effect.
arrestins to the receptor complex,96 which in turn promotes receptor internalisation.
By artificially binding S1P1R on lymphocytes, ozanimod (1) first
93–95
Binding to S1PR1 leads to agonist recruitment of beta-
97,98
As a result, cells no longer respond to the gradient and remain within the LNs, resulting
in pharmacodynamic effects characterized by a significant but rapidly reversible
97
reduction in circulating lymphocyte subsets.
Downregulation of the lymphocyte
expressed S1PR1 prevents their ability to respond to the S1P gradient and egress from
peripheral
lymphoid tissues. This results in a “functional antagonism” and reduces
circulating lymphocytes, including auto-reactive lymphocytes, preventing trafficking to
10
sites of inflammation and contribution to disease.
The effect of ozanimod (1) is
primarily observed on naïve and central memory B and T lymphocytes expressing the
99
chemokine receptor CCR7.
In clinical studies, ozanimod (1) was found to produce manageable chronotropic
cardiac effects at initiation followed by expected reductions in peripheral blood
100
lymphocyte count.
by implementation of drug titration for the first 4–5 days of treatment.
is consistent with transient agonism and subsequent functional antagonism of S1PR1.
The pharmacodynamic reduction in heart rate can be circumvented
101,102
This profile
98
It
is worth mentioning that all agents that engage S1PR1 will have some form of cardiac
98
effect.
The possible involvement of S1PR3 in humans remains unclear and new
modulators such as siponimod and ozanimod (1) with minimal S1PR3 binding does not
103,104
prevent first-dose cardiac effects.
Although the internalization of S1PR1 in response to ligand binding that leads to
functional antagonism is well established, evidence suggests that the binding of ozanimod
(1) to S1PR5 may not lead to receptor down-modulation or halt signaling in the same
98
manner.
Ozanimod (1) may act as an agonist for S1PR5, although inhibition by non-
internalization mechanism remains a possibility.
Ozanimod (1) may also act through a completely different mechanism. Multiple
S1P receptors are found on endothelial surfaces and play a role in regulating endothelial
76
function and stabilization.
90
cellular junctions.
As a S1PR1 agonists, ozanimod (1) induced “tightening” of cell
Specifically, stimulation of S1PR1 is believed to enhance
junctions, inhibiting trans-endothelial migration and blocking lymphocyte egress from the
42,105
lymph node.
Consequently, lymphocytes are trapped, decreasing circulating
lymphocyte counts. Research showed that upon withdrawal of the agonist agent, the
106
permeability is restored and lymphocyte trafficking resumes.
In addition to the effect of ozanimod (1) on circulating lymphocytes, another
mode of action has been proposed in the applicability of the drug as a neuroprotective
agent. This observation was based on a study in which ozanimod (1) showed the exertion
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Chemistry and Pharmacology of Drug Discovery
of a beneficial effect on experimental autoimmune encephalomyelitis (EAE) mice even
107
when absolute lymphocyte count (ALC) was normal.
Ozanimod (1) can readily cross
the blood–brain barrier (BBB) and thus potentially exerts beneficial effects by directly
establishing interactions with brain cells, possibly via S1PR5 signaling. Studies in mice
have shown that ozanimod (1) reduces axonal damage, thereby preserving CNS tissue
108
morphology after induced demyelination.
effects of Ozanimod were tested in ex vivo studies in EAE brains.
The anti-inflammatory and neuroprotective
98
Ozanimod (1)
treatment ameliorated EAE-driven striatal glutamatergic synapse alterations in an S1PR1dependent manner and lowered the expression level of pro-inflammatory markers in EAE
107
brain slices and microglial cell cultures.
In fact, the ability to cross the blood–brain barrier for all S1P receptor
modulators is probably one of the most important features that makes them a potential
combinatory treatment for both MS and IBD. The blood–brain barrier that resists drugs
penetrating might be the true “barrier” for relating IBD and MS together.
from
109
The
questions we raised early in this chapter regarding TNF and IFN-β treatment might find
answer by bearing the “barrier” hypothesis in mind. It is possible that the efficacy
an
discordance of TNF blockade in MS compared with IBD is the inability of TNF
antagonists to pass through the BBB to neutralize and prevent TNF mediated injury.
110
The case for why IFN-β works for MS but seem to exacerbate IBD patients is more
complicated. Researchers have found IFN-β has proinflammatory functions and
aggravates the pathogenesis of Th17-mediated inflammatory disease with only exception,
109,111
MS.
It is hypothesized that IFN-β only has an indirect effect in MS by tightening the
blood–brain barrier and resisting inflammatory cells or cytokines across rather than
treating MS itself directly.
109,111,112
While there are no direct data on the effect of
ozanimod (1) on BBB integrity in MS, another S1PR modulator siponimod has been
shown to have beneficial effects on occluding and zonula occludens-1 in a mouse model
113
of traumatic brain injury.
In addition, cellular and animal studies of fingolimod and
siponimod have demonstrated a range of effects including actions on astrocytes and
98,114–116
microglia and involvement in remyelination and repair.
Together these evidence
suggested that positive effects on tight junction (TJ) and BBB integrity as well as
98
neuroprotection may be a class effect of S1PR modulators.
3. Drug Metabolism and Pharmacokinetics
Ozanimod (1) does not require in vivo phosphorylation for activation.
by multiple enzymes to form two major active plasma metabolites [CC112273 (14) and
CC1084037 (5)], a major inactive plasma metabolite (RP101124) and several minor
active plasma metabolites (RP101075, RP101988, RP101442, RP112289, and
RP112509).
approval of ozanimod (1) was initially delayed for 2 years by insufficient preclinical
58
108
It is metabolized
All metabolites show similar selectivity for S1PR1 and S1PR5. The FDA
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Chapter 11. Ozanimod (Zeposia)
characterization of the active metabolite CC112273 (14), causing billions of dollars of
lost sales. The ozanimod (1) example illustrate the need for conducting timely
radiolabeled human metabolites studies and assessment of exposure coverage during drug
development (Figure 4).58
Figure 4. Structures of ozanimod’s major metabolites CC112273 (14) and CC1084037
(5)
Ozanimod (1) causes a dose-dependent and reversible reduction in the ALC. In a
7-day multiple ascending dose regimen, the median reduction in ALC was 14%, 49% and
68% respectively, for doses of 0.3 mg, 1 mg, and 2 mg. ALC returned to normal ranges
within 6 days of stopping. Though patients experiencing excess S1P modulatory effects
100
can experience lymphopenia,
rapid lymphocyte recovery.
with a short half-life of 19 h, ozanimod (1) allows for
77
Careful review of events in clinical trials further indicated
that severe lymphopenia is not a risk, and is manageable with dose adjustment or
117–119
interruption, and is not associated with serious adverse events.
Ozanimod (1) is metabolized by three primary pathways, including aldehyde
dehydrogenase and alcohol dehydrogenase, cytochrome P450 isoforms 3A4 and 1A1, and
reductive metabolism by gut microflora. The primary metabolite RP101075 is further
metabolized to form major active metabolite CC112273 (14) by monoamine oxidase B,
which further undergoes reduction by carbonyl reductases to form CC1084037 (5) or
CYP2C8-mediated oxidation to form RP101509. CC1084037 (5) is oxidized rapidly to
form CC112273 (14) by aldo-keto reductase 1C1/1C2 and or 3β-and 11β-hydroxysteroid
dehydrogenase and this reversible oxidoreduction between two active metabolites favors
58
CC112273.
Preclinical studies have shown that the pharmacokinetic properties of the minor
active metabolites (RP101988 and RP101075) are similar to those of ozanimod (1) with
98,120
similar affinities for S1PR1 and 5.
The two major metabolites are CC112273 and
CC1084307. Approximately 94% of total circulating active drug is made up of Ozanimod
(6%), CC112273 (73%) and CC1084037 (15%). The areas under the concentration-time
curves (AUCs) of CC112273 and CC1084037 are 13-fold and 2.5-fold greater than that
58
of ozanimod (1).
CC112273 is several folds less potent than Ozanimod for S1PR1 and 5
and is thought to account for the majority of ozanimod (1) activity in humans owing to its
58
relative abundance.
The less abundant major active metabolite CC1084307 is about 10
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