Preclinical Studies Suggest FTY720 Mechanisms in Multiple Sclerosis May Include Direct Activity in the Brain
· Preclinical studies suggest FTY720 stimulates cells that may help reduce neurodegeneration and enhance repair of the CNS affected by multiple sclerosis
· Separately, analyses from the six-month multiple sclerosis Phase II clinical study found that the proportion of patients with clinical depression was significantly lower in the FTY720 groups compared to placebo
· FTY720 is a novel oral drug currently in a worldwide Phase III clinical development program as a once-daily disease modifying therapy for relapsing MS
EAST HANOVER, NJ, May 3, 2007 - New preclinical data, presented at the American Academy of Neurology (AAN) annual meeting in Boston, reflect the expanding understanding of FTY720's (fingolimod) mechanism of action in multiple sclerosis (MS), suggesting direct beneficial effects in the brain. The data suggest that FTY720 may have the potential to reduce neurodegeneration and enhance repair of the central nervous system (CNS) by modulating S1P receptors expressed on brain cells. Separately, new clinical data presented from the six-month Phase II study found that the proportion of patients with clinical depression was significantly lower in the FTY720 groups compared to placebo.
These new preclinical data add to a growing body of evidence that FTY720 has multiple, specific mechanisms of action. The ongoing Phase III clinical development program includes comprehensive monitoring to further understand the clinical and safety implications of these mechanisms of action.
MS is a progressive and debilitating disorder of the CNS that frequently affects young people, women twice as often as men. It is caused by the destruction of myelin, which helps neurons carry electrical signals in the brain. MS is the most common inflammatory and neurodege nerative disorder of the CNS, causing problems with muscle control and strength, vision, balance, sensation and mental function. MS typically presents in relapsing forms involving acute self-limiting attacks of neurological dysfunction (or "relapses") followed by complete or partial restoration of functions.
FTY720's previously known activity is based on its ability to bind to the sphingosine 1-phosphate receptor-1 (S1P-R1) on circulating lymphocytes (white blood cells). This activity reversibly traps a proportion of lymphocytes in the lymph nodes, reducing the number of inflammatory T-cells circulating in the bloodstream and in the CNS.
One of the preclinical studies presented at AAN evaluated FTY720's ability to activate S1P receptors on astrocytes in cell culture. Astrocytes are known to play an active role in nervous tissue repair, and to regulate the permeability of the blood brain barrier. The study findings indicate that FTY720 activates S1P receptors on astrocytes, stimulating intracellular pathways that regulate a variety of functions, such as cell proliferation and migration. (Muellershausen et al)
A second study, also conducted in cell culture, demonstrated that FTY720 improved the survival and increased the number of immature and mature oligodendrocytes - cells that help form myelin in the CNS. Stimulation of S1P receptors on oligodendrocytes may help limit demyelination and/or promote myelin repair. (Barske et al)
In the third study, conducted in an established animal model of MS [experimental autoimmune encephalomyelitis (EAE) in rats], researchers found that FTY720 directly administered in the rat brain significantly suppressed the severity of clinical EAE, suggesting additional mechanisms of action independent of lymphocyte depletion. In imaging studies, enhanced myelination and axonal protection associated with the clinical effects were confirmed in animals receiving oral FTY720. (Schubart et al )
Clinical results in depression (Kappos et al)
Data from the six-month placebo-controlled Phase II study of once-daily oral FTY720 in patients with MS found that the proportion of patients with clinical depression was significantly lower in the FTY720 groups at six months compared to placebo. Depression is a common co-morbid condition in people with MS; the presence of depression in MS may reduce adherence to disease-modifying therapy and lead to higher rates of treatment discontinuation.
The Phase II study included 281 patients, randomized to receive FTY720 1.25 mg, FTY720 5 mg, or placebo. Depression was evaluated in 239 patients using the Beck Depression Inventory - Second Edition (BDI-II). BDI-II scores of 14 or more suggest clinical depression. At baseline, mean BDI-II scores were 9.3 for patients randomized to receive FTY720 1.25 mg, 8.0 for patients randomized to receive FTY720 5 mg, and 9.1 for patients randomized to receive placebo. At month six, patients receiving FTY720 1.25 mg had the most improvement in depression symptoms (BDI-II = 7.9, mean change from baseline = -1.45). Patients receiving FTY720 5 mg had no change in mean BDI-II scores, and patients receiving placebo showed worsening (BDI-II=10, mean change from baseline = +0.94). The proportions of patients with BDI-II scores indicating clinical depression were significantly lower in both FTY720 groups when compared with the placebo group at month six: 33% of patients receiving placebo versus 17% of patients receiving FTY720 1.25 mg (p=0.0176) and 19% of patients receiving FTY720 5 mg (p=0.0407).
FTY720 is a novel oral drug that is currently in a worldwide Phase III clinical development program as a once-daily, disease modifying therapy for relapsing MS. Previously reported Phase II results showed that patients treated with FTY720 had a significant reduction in relapses and in inflammation as measured on Magnetic Resonance Imaging (MRI) compared to pl acebo at six months and that low disease activity was maintained over two years. Up to 77% of patients remained relapse free and more than 80% of patients were free from lesions showing active inflammation on MRI after two years of continuous FTY720 treatment. Patients who received placebo for the first six months of the study also experienced a marked improvement after switching to FTY720 in the extension, and low disease activity was sustained through month 24.
The Phase III clinical trials program includes FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis), a 24-month, randomized, double-blind, placebo-controlled study program that plans to include over 2,000 patients worldwide with the relapsing-remitting form of MS, and TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in RrMS), an international 12-month, randomized, double-blind study comparing FTY720 to Interferon-beta-1a (Avonex®, i.m. once weekly). For more information about the clinical trial program, including eligibility criteria and location of U.S. study sites, patients can call the following toll-free number: 866-788-3930, or visit www.MSClinicalTrials.com.
In the six-month placebo-controlled phase of the Phase II study, the most frequent adverse events reported for FTY720 were dose-dependent upper respiratory tract infections (mainly nasopharyngitis) and dyspnea, plus diarrhea and nausea. FTY720 treatment was associated with initial dose-dependent decreases in heart rate and expiratory air flow. Clinically asymptomatic increases in alanine aminotransferase (liver enzyme) and an increase in blood pressure were also observed. No unexpected adverse events emerged in patients treated for up to 24 months compared with the six-month placebo-controlled phase. There was no further elevation of blood pressure with continued treatment beyond the effect seen at six months. The ongoing Phase III study program includes comprehensive monitoring, which will provide further characterization of the safety profile of FTY720.
This release contains certain forward-looking statements relating to Novartis' business, which can be identified by the use of forward-looking terminology such as "may," "suggest," "suggesting," "potential," "growing body of evidence," "plans to include" or similar expressions, or by express or implied statements regarding the potential approval of FTY720 by health authorities for marketing, whether or not FTY720 will be the first orally effective MS treatment, the potential health effects or long-term impact of a patient's use of FTY720, or potential future revenue from FTY720. Such forward-looking statements reflect the current views of Novartis regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with FTY720 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that FTY720 will be approved for any indications or labeling in any market. Neither can there be any guarantee that, if approved, it will be the first orally effective MS treatment approved. Neither can there be any guarantee regarding the health effects or long-term impact of a patient's use of FTY720. Neither can there be any guarantees that FTY720 will reach any particular levels of revenue. In particular, management's expectations regarding FTY720 could be affected by, among other things, unexpected clinical trial results, including new clinical trial results and additional analysis of existing results; unexpected regulatory actions or delays or government regulation generally; competition in general; Novartis' ability to obtain or maintain patent or other proprietary intellectual property protection; government, industry and general public pricing pressures, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
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AAN 2007 -FTY720 Posters
1) [P06.085] Oral FTY720 in Relapsing Multiple Sclerosis (MS): Impact on Patient-Reported Depression, as Measured by the Beck Depression Inventory II in a 6-month, Placebo-Controlled Phase II Study
Date: Thursday, May 3, 2007 7:00 AM
Location: Exhibit Hall A - Poster Sessions VI: Multiple Sclerosis and Related Diseases: Therapeutics (7:00 - 10:00 AM)
Objective: To examine the effect of FTY720 on patient-reported depression. BACKGROUND: Current disease-modifying MS therapies have a variable impact on depression, a common symptom in MS. FTY720, a new oral sphingosine-1-phosphate receptor modulator, has shown reductions in relapse rate of >50% and MRI activity of up to 80% vs placebo (PL) during a 6-month, Phase II study in relapsing MS (Kappos et al. N Engl J Med 20 06;355:1124-40).
Conclusion/Relevance: Evaluation of depression in MS may contribute to the assessment of overall effects of innovative treatments. At M6, fewer patients receiving FTY720, compared with PL, reported depression on the BDI-II or as an AE. Mean BDI-II scores were low in all groups. Nevertheless, patients receiving FTY720 1.25 mg, compared with PL, showed significant improvement in this score between baseline and M6.
2) [P07.101] CNS Mediated Effects of FTY720 (Fingolimod) in EAE
Date: Thursday, May 3, 2007 11:30 AM
Location: Exhibit Hall A - Poster Sessions VII: Multiple Sclerosis and Related Diseases: Animal Models II (11:30 AM - 2:30 PM)
Objective: To determine the centrally mediated effects of FTY720 (Fingolimod) in experimental autoimmune encephalomyelitis (EAE) in DA rats, an animal model of multiple sclerosis.
Conclusion/Relevance: These studies suggest that the mechanism of action of FTY720 may involve beneficial direct CNS effects in addition to the well-described effect on reducing T cell infiltration into the CNS. This raises the possibility that FTY720 might also have protective effects in progressive stages of multiple sclerosis.
3) [P08.135] FTY720 (Fingolimod) Regulates Astrocyte Signaling and Migration
Date: Thursday, May 3, 2007 4:00 PM
Location: Exhibit Hall A - Poster Sessions VIII: Multiple Sclerosis and Related Diseases: Immunology II (4:00 - 7:00 PM)
Objective: The aim of our study was to define which sphingosine-1-phosphate receptor (S1P-Rs) subtypes are responsible for mediating FTY720 action on brain cells, specifically on astrocytes.
Conclusion/Relevance: We report that FTY720P activates S1P-Rs on astrocytes, thereby stimulating a number of intracellular signals and cell migration. These findings indicate that FTY720 has multiple S1P-R-specific modes of action, beyond immunomodulation, which may contribute to its effectiveness in multiple sclerosis.
4) [P08.132] FTY720 (Fingolimod) Enhances the Number of Progenitor & Oligodendrocytes
Date: Thursday, May 3, 2007 4:00 PM
Location: Exhibit Hall A - Poster Sessions VIII: Multiple Sclerosis and Related Diseases: Immunology II (4:00 - 7:00 PM)
Objective: We investigated the role of sphingosine-1-phosphate receptors (S1P-Rs) on oligodendrocytes and determined the direct effects of FTY720 on increasing oligodendrocyte numbers.
Conclusion/Relevance: We have shown that FTY720P increases oligodendrocyte numbers in both immature and mature lineages. We propose that FTY720P-mediated stimulation of S1P-Rs on oligodendrocytes may help limit demyelination and/or promote remyelination in multiple sclerosis. These direct effects of FTY720 on oligodendrocytes may contribute to its effectiveness in multiple sclerosis and limit disease progression.