The most exciting new therapy being discussed at ECTRIMS 2006 is (in my view) fingolimod or FTY720.

This oral drug is beginning phase III trials now. One trial 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 (double-blind, 24 month) trial is recruiting 1250 patients comparing two doses of the drug to placebo.

Yet another single-blind?, 24 month trial 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, 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.

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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
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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.
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Pharmacodynamic effects of oral fingolimod (FTY720)

R. Schmouder, S. Aradhye, P. O'Connor, L. Kappos (East Hanover, USA; Toronto, CAN; Basel, CH)

Background: Fingolimod is an oral sphingosine-1-phosphate (S1P) receptor modulator that reduced relapse rate by more than 50% and MRI inflammatory lesion activity by up to 80% compared to placebo at 6 months in a Phase II study in relapsing multiple sclerosis (MS) patients.

Low disease activity on fingolimod was maintained with continued treatment for up to 18 months. Interaction of fingolimod with S1P receptors induces a transient reduction in heart rate upon treatment initiation and inhibits the egress of lymphocytes from the lymph nodes.

Objectives: To describe the effects of fingolimod on peripheral lymphocyte counts and on heart rate, with special focus on doses currently used in the Phase III MS studies (0.5 and 1.25 mg/day).

Methods: We reviewed data from approximately 150 healthy volunteers (HV) and 134 MS patients treated with 0.5 or 1.25 mg fingolimod.

Results: In HVs receiving single-dose fingolimod, blood lymphocyte counts were reduced in a dose-dependent manner. In HVs receiving fingolimod 1.25 mg/day for 7 days, mean lymphocyte counts decreased from 1900 cells/mm3 at baseline to 400 cells/mm3 at day 7. After cessation of dosing, lymphocyte counts began to increase within 2–3 days and had recovered to 74% of baseline (mean 1400 cells/mm3) 4 weeks after the last dose (end of study).

In the Phase II MS study, the reduction in circulating lymphocytes with 1.25 mg fingolimod was similar to that seen in HVs. Lymphocyte counts remained stable over 12 months of continuous therapy (mean 570 cells/mm3 at month 12). There were no correlations between low lymphocyte counts and severe or serious infections under fingolimod treatment.

In both HV and MS patients, decrease in heart rate after the first dose of fingolimod was maximal between 4–5 h post-dose (a reduction of 10–13 bpm on average for 1.25 mg and 5 bpm for 0.5 mg), returning towards baseline with subsequent dosing.

In HVs there was no effect on circadian autonomic rhythm and the heart’s responses to intrinsic/extrinsic stimuli were intact. Of the 134 MS patients receiving 1.25 mg fingolimod in the Phase II study, symptomatic bradycardia was reported in only 1 patient and resolved without treatment.

Conclusion: Transient reduction in heart rate is a well-characterized biological effect of fingolimod and is clinically benign in HV and MS patients. Fingolimod induces a dose-dependent reduction in peripheral lymphocyte counts, an effect that is thought to contribute to its therapeutic effects in MS.
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Oral fingolimod maintains and restores neuronal function in demyelinating models of multiple sclerosis, as assessed by somatosensory and visual evoked potentials

B. Balatoni, M.K. Storch, R. Weissert, C.A. Foster (Vienna, Graz, A; Tubingen, D)

Background: Fingolimod (FTY720) is an orally-active sphingosine 1-phosphate (S1P) receptor modulator under development for the treatment of multiple sclerosis (MS). During a phase II trial in relapsing MS, it reduced clinical relapse rate by more than 50% and inflammatory lesion activity on magnetic resonance imaging by up to 80%. Phase III studies are ongoing.

Aim: To elucidate how FTY720 exerts its beneficial effects in the central nervous system (CNS), we compared functional parameters of nerve conductance with morphological features in the DA rat model of experimental autoimmune encephalomyelitis (EAE) under prophylactic and therapeutic settings.

Methods: EAE was induced with myelin oligodendrocyte glycoprotein (MOG) or syngeneic neuroantigen. Prophylactic oral treatment with FTY720 (0.3 to 0.4 mg/kg) or vehicle started on day 0 and continued for 3 weeks, while therapeutic treatment was initiated on day 25 or 40 post-immunization.

Clinical scores were assessed daily; visual and somatosensory evoked potentials (VEP, SEP) were recorded prior to perfusion-fixation; histological and immunocytochemical analyses were performed on the brain, optic nerves and spinal cord to assess inflammation, demyelination, axonal loss and blood-brain-barrier (BBB) integrity.

Results: FTY720 prophylaxis completely protected against the emergence of EAE symptoms, electrophysiological disturbances and pathology in the CNS. Therapeutic treatment reversed severe neurological deficits in established EAE induced by syngeneic myelin proteins as well as MOG.

In parallel to these clinical benefits, FTY720 restored and normalized the functional responses to SEP and VEP stimulation. Neuronal function and clinical efficacy correlated with a reversal of BBB leakiness and a reduction of inflammatory infiltrates, actively demyelinating lesions and axonal loss.

Conclusions: The effectiveness of FTY720 in reversing clinical disease and restoring nerve conductance is likely due to several contributing factors. Evidence thus far support its role in the reduction of inflammation and preservation of BBB integrity. FTY720 may also act via S1P receptors expressed by glial cells and/or neurons in the CNS to promote endogenous repair mechanisms that complement its immunomodulatory action.

Thanks for posting it Mark.

I am crossing my "fingo's" for Fingolimod (Sorry, I couldnt help it )

Thanks Mark. A friend of mine saw something about this drug one night on TV. He seemed to think it sounded promising. I hope it pans out, and doesn't have too many side effects.

Virginia

Greetings Mark!!

This from today's news:


Today: September 28, 2006 at 5:20:17 PDT

MS Drug Treatment Shows Promise

ASSOCIATED PRESS

EAST HANOVER, N.J. (AP) - Novartis Pharmaceuticals Corp., the U.S. unit of Swiss drugmaker Novartis AG, said Thursday that at least three out of four patients given an experimental multiple sclerosis treatment were free of relapses for more than two years.

The company released data from a mid-stage clinical study showing that 77 percent of MS patients given the treatment FTY720 over two years remained free of relapses.

Multiple sclerosis, which affects more than 2.5 million people worldwide, is an incurable disease which causes the body's immune system to destroy the insulation of nerve fibers.

More than 80 percent of patients taking the drug were found not to have active inflammation according to medical imaging scans. The company also said that patients who had been given a placebo for the first six months of the study showed a marked improvement after they were switched to the treatment, an improvement that was sustained out to the 24th month of the study.

Novartis developed FTY720 after licensing the compound from Mitsubishi Pharma. The oral drug is currently in late-stage clinical trials.

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Ah, Mark/xo posting and commenting on research news in his usual superb way... feels like home!

Now if only Cat Dancer, Mike/Grassman, renee, and a few other AWOL luminaries would show up, it'd be even more real.

Nancy T.

Thanks Mark. even though I'm not RRMS anymore, I still hold hope for this drug, that it may help me, even though I am at a plateau with my MS, thanks to LDN, I think.

My Son sent me the yahoo news report, this morning, and he never does that.

Sounds promising.

I was on another board and when I read the latest on this drug, I said "where's Mark when you need him most?"

Now I guess I have to go away and pick apart your information.

This does look promising though, doesn't it?

Cherie