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Siponimod Chips Away at Progressive MS
Leading Edge
Bench to Bedside Siponimod Chips Away at Progressive MS Erin E. Longbrake and David A. Hafler
Yale University, New Haven, CT, USA; Correspondence: [email protected] https://dx.doi.org/10.1016/j.cell.2019.11.034 NAME
Without Siponimod
Siponimod APPROVED FOR
Lymphocytes
Relapsing and active secondary progressive multiple sclerosis S1P
Lymph node
With Siponimod
Lymphocyte egress
S1P1/5
TYPE
Small Molecule MOLECULAR TARGETS
Sphingosine 1-phosphate receptors 1 and 5 Siponimod
X
S1P1/5
S1P1/5 downregulation
CELLULAR TARGETS
Lymphocytes Decreased lymphocyte egress
Progressive multiple sclerosis (PMS) causes slow accumulation of neurologic disability and has been refractory to treatment with the immunomodulatory medications that effectively control relapsing MS. Siponimod modestly slowed the rate of disability progression among PMS patients who had inflammatory disease activity, evidenced by new or gadolinium-enhancing MRI lesions.
Clinical trials
EFFECTS ON TARGETS
Siponimod binds S1P receptors 1 and 5 on lymphocytes, leading to receptor internalization and degradation. In the absence of these receptors, lymphocyte egress from lymphoid organs is blocked. Siponimod was engineered to eliminate binding of S1PR3, thought to mediate cardiac side effects, and to shorten the drug’s half-life. Siponimod may also have direct neuroprotective effects mediated by direct binding of S1P receptors on oligodendrocytes, astrocytes, microglia, and CNS neurons. DEVELOPED BY
Novartis Pharmaceuticals
Clinical effect of Siponimod
Progressive MS clinical trials
Benefiting patients
8 trials 23 trials
Negative results Positive results
Positive results
~21%
Reduction in disability progression
Did not confirm
21%
Waiting to be confirmed Confirmed and approved
Patients with active disease
1998
FTY720, a functional antagonist of most S1P receptors, recognized as able to sequester lymphocytes and ameliorate animal models of MS
2019
2000
FDA approval of siponimod for relapsing and active secondary progressive MS
2010 2004
Egress of lymphocytes from thymus and peripheral lymphoid organs discovered to depend on S1P receptor 1
1995
Patients with progressive MS
Successful phase 3 trials of FTY720 in relapsing MS; FDA approval for FTY720 (fingolimod)
2005
2018
Results from EXPAND phase 3 trial of siponimod published
2010
2015
2020
References for further reading and a declaration of interests for E.E.L. and D.A.H. are available with this article online: www.cell.com/cell/abstract/S0092-8674(19)31319-4.
1440 Cell 179, December 12, 2019 © 2019 Published by Elsevier Inc.
Bench to Bedside Siponimod Chips Away at Progressive MS Erin E. Longbrake and David A. Hafler
Yale University, New Haven, CT, USA; Correspondence: [email protected] https://dx.doi.org/10.1016/j.cell.2019.11.034 NAME
Without Siponimod
Siponimod APPROVED FOR
Lymphocytes
Relapsing and active secondary progressive multiple sclerosis S1P
Lymph node
With Siponimod
Lymphocyte egress
S1P1/5
TYPE
Small Molecule MOLECULAR TARGETS
Sphingosine 1-phosphate receptors 1 and 5 Siponimod
X
S1P1/5
S1P1/5 downregulation
CELLULAR TARGETS
Lymphocytes Decreased lymphocyte egress
Progressive multiple sclerosis (PMS) causes slow accumulation of neurologic disability and has been refractory to treatment with the immunomodulatory medications that effectively control relapsing MS. Siponimod modestly slowed the rate of disability progression among PMS patients who had inflammatory disease activity, evidenced by new or gadolinium-enhancing MRI lesions.
Clinical trials
EFFECTS ON TARGETS
Siponimod binds S1P receptors 1 and 5 on lymphocytes, leading to receptor internalization and degradation. In the absence of these receptors, lymphocyte egress from lymphoid organs is blocked. Siponimod was engineered to eliminate binding of S1PR3, thought to mediate cardiac side effects, and to shorten the drug’s half-life. Siponimod may also have direct neuroprotective effects mediated by direct binding of S1P receptors on oligodendrocytes, astrocytes, microglia, and CNS neurons. DEVELOPED BY
Novartis Pharmaceuticals
Clinical effect of Siponimod
Progressive MS clinical trials
Benefiting patients
8 trials 23 trials
Negative results Positive results
Positive results
~21%
Reduction in disability progression
Did not confirm
21%
Waiting to be confirmed Confirmed and approved
Patients with active disease
1998
FTY720, a functional antagonist of most S1P receptors, recognized as able to sequester lymphocytes and ameliorate animal models of MS
2019
2000
FDA approval of siponimod for relapsing and active secondary progressive MS
2010 2004
Egress of lymphocytes from thymus and peripheral lymphoid organs discovered to depend on S1P receptor 1
1995
Patients with progressive MS
Successful phase 3 trials of FTY720 in relapsing MS; FDA approval for FTY720 (fingolimod)
2005
2018
Results from EXPAND phase 3 trial of siponimod published
2010
2015
2020
References for further reading and a declaration of interests for E.E.L. and D.A.H. are available with this article online: www.cell.com/cell/abstract/S0092-8674(19)31319-4.
1440 Cell 179, December 12, 2019 © 2019 Published by Elsevier Inc.