xo++
10-02-2006, 06:00 PM
The most exciting new therapy being discussed at ECTRIMS 2006 (http://www.akm.ch/ectrims2006/) is (in my view) fingolimod or FTY720.
This oral drug is beginning phase III trials now. One trial (http://www.clinicaltrials.gov/ct/show/NCT00340834?order=1) is recruiting 1275 patients in a double-blind, 12 month trial comparing the drug's effectiveness to interferon ß-1a (Avonex or Rebif?).
The phase III (http://www.clinicaltrials.gov/ct/show/NCT00289978?order=3) (double-blind, 24 month) trial is recruiting 1250 patients comparing two doses of the drug to placebo.
Yet another single-blind?, 24 month trial (http://www.clinicaltrials.gov/ct/show/NCT00355134?order=2) is recruiting 960 patients comparing two doses of the drug to placebo.
Only the phase III trial appears to be using disability progression as an outcome. As is typical, Novartis is using relapse rate reduction and reduction in enhancing lesions as the primary outcome, since it is easier to demonstrate impact on these measures.
Briefly summarizing the abstracts below (broken into two posts), in the phase II trial, both doses of fingolimod reduced new lesion activity by about 80% and reduced relapse rates by greater than 50%. Side effects were much higher in the higher dose group, but only the lower dose, and a still lower dose will be tested in the upcoming trials.
The drug (particularly at the higher dose) did appear to cause an increase in some infections, and what is described below as "benign" bradycardia (slower heart rate).
But the drug only affects a subset of T-cells, leaving most other T-cells in the periphery to combat infection.
The most exciting suggestion (to me) below is that fingolimod may reverse disease and restore function by directly acting on receptors on nerves in the central nervous system promoting repair in the brain and spinal cord.
___
Oral fingolimod (FTY720) in relapsing multiple sclerosis: 24-month results of the Phase II study
L. Kappos, J.P. Antel, G. Comi, X. Montalban, E.W. Radue, A. de Vera, H. Pohlmann, P. O’Connor on behalf of the FTY720D2201 Study Group
Background: In a 6-month (M), placebo-controlled (PL-C) study including 281 patients with relapsing MS (89% RRMS, 11% SPMS patients), the oral sphingosine-1-phosphate receptor modulator fingolimod significantly reduced inflammatory disease activity on MRI by up to 80% and relapses by more than 50% at both doses. The annualized relapse rate (ARR) was 0.77 with PL versus 0.35 with 1.25 mg (P=0.009) and 0.36 with 5 mg fingolimod (P=0.014).
Objective: To report the M24 safety and efficacy results of this Phase II study.
Methods: 250 of 255 patients completing the 6-M PL-C phase entered the extension. Patients on fingolimod continued their originally-assigned treatment; those on PL were re-randomized to fingolimod (PL-fingolimod groups). Evaluations were scheduled monthly during M0-6 and 3-monthly during M7-24.
Between the M15 and M24 visit all patients receiving 5 mg were switched to 1.25 mg. The extension is ongoing with all patients on 1.25 mg fingolimod. The original treatment allocation was not disclosed to the sites until all patients completed M24 visit.
Results: The M0-24 ARR was 0.20 in the continuous fingolimod and 0.33 in the PL–fingolimod groups (6M on PL, 18M on fingolimod). At M24, 84% of patients in the continuous fingolimod and 85% in PL-fingolimod groups were free of Gd+ lesions. 79% of patients in the continuous fingolimod and 78% in the PL-fingolimod groups were free of 3-M confirmed disability progression.
Nasopharyngitis and influenza were the most frequent adverse events reported. Clinically asymptomatic increases in ALT and increase in blood pressure (average of 5 mmHg within first the 6 months remaining stable thereafter) were also observed.
Conclusions: At 6 months, fingolimod reduced disease activity on MRI up to 80% and relapse rate by more than 50% versus PL. Over 2 years of treatment, disease activity (MRI and clinical) remained low in the continuous fingolimod groups. In patients switching from placebo to fingolimod, disease activity consistently decreased after the switch and remained low thereafter.
No unexpected side-effects emerged in patients treated for up to 24 months compared with the 6-month placebo-controlled phase. These positive results support further evaluation of fingolimod as an oral treatment option in the ongoing Phase III program in RRMS.
Study supported by Novartis Pharma AG
________
The mode of action of Fingolimod (FTY720), an oral sphingosine 1-phosphate receptor modulator that is highly effective in human multiple sclerosis (Phase II)
V. Brinkmann, B. Metzler, M. Matloubian, H. Mitruecker (Basel, CH; San Francisco, USA; Berlin, D)
Fingolimod (FTY720), an oral immunomodulator with a novel mechanism of action, has shown excellent efficacy in human multiple sclerosis (MS) in a Phase II study. Six months data showed a highly significant reduction in the relapse rate and in the number of brain lesions detected by MRI scan, as well as a longer time to first relapse.
Mechanistic studies show that Fingolimod does not impair T- and B-cell activation, proliferation and effector function, but interferes with cell traffic between lymphoid organs and blood. Fingolimod, after phosphorylation, acts as high affinity agonist at the G protein-coupled sphingosine 1-phosphate receptor-1 (S1P1) on lymphocytes, thereby down-modulating the receptor.
This renders the cells unresponsive to the serum lipid sphingosine 1-phosphate (S1P), depriving them of an obligatory signal required to transmigrate through the sinus-lining endothelium in the lymph nodes (LN) and to egress into efferent lymph and blood.
This process reduces the recirculation of disease-relevant auto-reactive T-cells from their site of activation in the LN to the central nervous system (CNS) and, as a consequence, abrogates the inflammatory process. Since blood lymphocytes comprise only about 2% of the total lymphocyte pool of the body, the trapping of T-cell subsets does not result in detectable cell accumulation in LN.
Fingolimod differentially affects T-cell subsets depending on their recirculation characteristics. The drug effectively traps naive T-cells (Tn) and central memory T-cells (Tcm) in the LN, but spares peripheral effector memory T-cells (Tem). This relates to the fact that Tem do not express the LN homing receptors CD62L and CCR7 and, thus, do not traffic through LN.
These data suggest that pathogenic T-cells may primarily reside within the Tcm subset which could cross-react on autoantigen (AA) in draining LNs and, in the absence of Fingolimod, would recirculate to the CNS.
In contrast, peripheral Tem (i.e. in gut epithelial surfaces, small intestine lamina propria, lung, liver, kidney, peritoneum, bone marrow, blood) would not reach the CNS but could provide local defense against infection. Accordingly, Fingolimod did not affect clearance of Listeria monocytogenes infection in mice.
The available data establish S1P1 as the key target of Fingolimod, and further identify the novel class of G-protein-coupled sphingosine 1-phosphate receptors as therapeutically relevant drug targets in autoimmune indications, including MS.
This oral drug is beginning phase III trials now. One trial (http://www.clinicaltrials.gov/ct/show/NCT00340834?order=1) is recruiting 1275 patients in a double-blind, 12 month trial comparing the drug's effectiveness to interferon ß-1a (Avonex or Rebif?).
The phase III (http://www.clinicaltrials.gov/ct/show/NCT00289978?order=3) (double-blind, 24 month) trial is recruiting 1250 patients comparing two doses of the drug to placebo.
Yet another single-blind?, 24 month trial (http://www.clinicaltrials.gov/ct/show/NCT00355134?order=2) is recruiting 960 patients comparing two doses of the drug to placebo.
Only the phase III trial appears to be using disability progression as an outcome. As is typical, Novartis is using relapse rate reduction and reduction in enhancing lesions as the primary outcome, since it is easier to demonstrate impact on these measures.
Briefly summarizing the abstracts below (broken into two posts), in the phase II trial, both doses of fingolimod reduced new lesion activity by about 80% and reduced relapse rates by greater than 50%. Side effects were much higher in the higher dose group, but only the lower dose, and a still lower dose will be tested in the upcoming trials.
The drug (particularly at the higher dose) did appear to cause an increase in some infections, and what is described below as "benign" bradycardia (slower heart rate).
But the drug only affects a subset of T-cells, leaving most other T-cells in the periphery to combat infection.
The most exciting suggestion (to me) below is that fingolimod may reverse disease and restore function by directly acting on receptors on nerves in the central nervous system promoting repair in the brain and spinal cord.
___
Oral fingolimod (FTY720) in relapsing multiple sclerosis: 24-month results of the Phase II study
L. Kappos, J.P. Antel, G. Comi, X. Montalban, E.W. Radue, A. de Vera, H. Pohlmann, P. O’Connor on behalf of the FTY720D2201 Study Group
Background: In a 6-month (M), placebo-controlled (PL-C) study including 281 patients with relapsing MS (89% RRMS, 11% SPMS patients), the oral sphingosine-1-phosphate receptor modulator fingolimod significantly reduced inflammatory disease activity on MRI by up to 80% and relapses by more than 50% at both doses. The annualized relapse rate (ARR) was 0.77 with PL versus 0.35 with 1.25 mg (P=0.009) and 0.36 with 5 mg fingolimod (P=0.014).
Objective: To report the M24 safety and efficacy results of this Phase II study.
Methods: 250 of 255 patients completing the 6-M PL-C phase entered the extension. Patients on fingolimod continued their originally-assigned treatment; those on PL were re-randomized to fingolimod (PL-fingolimod groups). Evaluations were scheduled monthly during M0-6 and 3-monthly during M7-24.
Between the M15 and M24 visit all patients receiving 5 mg were switched to 1.25 mg. The extension is ongoing with all patients on 1.25 mg fingolimod. The original treatment allocation was not disclosed to the sites until all patients completed M24 visit.
Results: The M0-24 ARR was 0.20 in the continuous fingolimod and 0.33 in the PL–fingolimod groups (6M on PL, 18M on fingolimod). At M24, 84% of patients in the continuous fingolimod and 85% in PL-fingolimod groups were free of Gd+ lesions. 79% of patients in the continuous fingolimod and 78% in the PL-fingolimod groups were free of 3-M confirmed disability progression.
Nasopharyngitis and influenza were the most frequent adverse events reported. Clinically asymptomatic increases in ALT and increase in blood pressure (average of 5 mmHg within first the 6 months remaining stable thereafter) were also observed.
Conclusions: At 6 months, fingolimod reduced disease activity on MRI up to 80% and relapse rate by more than 50% versus PL. Over 2 years of treatment, disease activity (MRI and clinical) remained low in the continuous fingolimod groups. In patients switching from placebo to fingolimod, disease activity consistently decreased after the switch and remained low thereafter.
No unexpected side-effects emerged in patients treated for up to 24 months compared with the 6-month placebo-controlled phase. These positive results support further evaluation of fingolimod as an oral treatment option in the ongoing Phase III program in RRMS.
Study supported by Novartis Pharma AG
________
The mode of action of Fingolimod (FTY720), an oral sphingosine 1-phosphate receptor modulator that is highly effective in human multiple sclerosis (Phase II)
V. Brinkmann, B. Metzler, M. Matloubian, H. Mitruecker (Basel, CH; San Francisco, USA; Berlin, D)
Fingolimod (FTY720), an oral immunomodulator with a novel mechanism of action, has shown excellent efficacy in human multiple sclerosis (MS) in a Phase II study. Six months data showed a highly significant reduction in the relapse rate and in the number of brain lesions detected by MRI scan, as well as a longer time to first relapse.
Mechanistic studies show that Fingolimod does not impair T- and B-cell activation, proliferation and effector function, but interferes with cell traffic between lymphoid organs and blood. Fingolimod, after phosphorylation, acts as high affinity agonist at the G protein-coupled sphingosine 1-phosphate receptor-1 (S1P1) on lymphocytes, thereby down-modulating the receptor.
This renders the cells unresponsive to the serum lipid sphingosine 1-phosphate (S1P), depriving them of an obligatory signal required to transmigrate through the sinus-lining endothelium in the lymph nodes (LN) and to egress into efferent lymph and blood.
This process reduces the recirculation of disease-relevant auto-reactive T-cells from their site of activation in the LN to the central nervous system (CNS) and, as a consequence, abrogates the inflammatory process. Since blood lymphocytes comprise only about 2% of the total lymphocyte pool of the body, the trapping of T-cell subsets does not result in detectable cell accumulation in LN.
Fingolimod differentially affects T-cell subsets depending on their recirculation characteristics. The drug effectively traps naive T-cells (Tn) and central memory T-cells (Tcm) in the LN, but spares peripheral effector memory T-cells (Tem). This relates to the fact that Tem do not express the LN homing receptors CD62L and CCR7 and, thus, do not traffic through LN.
These data suggest that pathogenic T-cells may primarily reside within the Tcm subset which could cross-react on autoantigen (AA) in draining LNs and, in the absence of Fingolimod, would recirculate to the CNS.
In contrast, peripheral Tem (i.e. in gut epithelial surfaces, small intestine lamina propria, lung, liver, kidney, peritoneum, bone marrow, blood) would not reach the CNS but could provide local defense against infection. Accordingly, Fingolimod did not affect clearance of Listeria monocytogenes infection in mice.
The available data establish S1P1 as the key target of Fingolimod, and further identify the novel class of G-protein-coupled sphingosine 1-phosphate receptors as therapeutically relevant drug targets in autoimmune indications, including MS.