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4SC's Vidofludimus Inhibits IL-17 Production by Interference With the JAK/STAT and NF-ï?«B Pathways

PLANEGG-MARTINSRIED, Germany--(BUSINESS WIRE)--May 9, 2011 - 4SC AG (Frankfurt, Prime Standard: VSC), a drug discovery and development company focused on autoimmune and cancer indications, has presented novel data on the mechanism of action of vidofludimus, an oral inhibitor of interleukin-17 (IL-17A and IL-17F) release and DHODH. These data show that vidofludimus inhibits STAT3 and NF-kB signaling pathways in murine colitis models and were presented at Digestive Disease Week, the world's largest gastroenterology conference, held from May 7-10, 2011 in Chicago, USA. In addition, final results from the previously announced vidofludimus Phase IIa study in inflammatory bowel disease (the 'ENTRANCE' trial) were also presented.

The novel mechanism of action data, generated in collaboration with Prof. Leo R. Fitzpatrick (Department of Pharmacology, Penn State College of Medicine, Hershey, PA), demonstrated the inhibition of IL-17 release, a key pro-inflammatory cytokine, as well as the attenuation of STAT3 and NF-kB signaling pathways, which play a prominent role in IL-17 production and intestinal inflammation. Vidofludimus has previously demonstrated inhibition of colonic IL-17 expression and murine colitis (Fitzpatrick et al, Inflammatory Bowel Diseases, 2010).

In mouse splenocytes, vidofludimus reduced the expression of phosphoproteins (JAK2, STAT3, and AKT1) involved in STAT3 signaling as well as the nuclear binding of STAT3. Vidofludimus did not reduce the phosphorylation or degradation of IkB, but inhibited nuclear binding of p65. Phospho STAT3 and p65 immunostaining was attenuated in leukocytes within the colons of TNBS mice treated with vidofludimus. Based on this data it is assumed that vidofludimus inhibits IL-17 production via interference with the JAK2/STAT3 and NF-κB pathways contributing to the demonstrated anti-colitis activity of this drug.

The Phase IIa ENTRANCE trial, which evaluated vidofludimus as a maintenance therapy to prevent future flare ups in inflammatory bowel disease patients, demonstrated an 88.5% total response rate versus an average placebo response rate of approximately 20% across published benchmark clinical trials. 53.9% (14 out of 26) of patients were complete responders, 34.6% (9 out of 26) of patients were partial responders, and 11.5% (3 out of 26) of patients were evaluated as non-responders. No variation in response rates across the sub-disease populations of Crohn's disease (85.7%) and ulcerative colitis (91.7%) was observed. Vidofludimus was safe and well tolerated by all patients.

Dr Bernd Hentsch, Chief Development Officer of 4SC, commented: 'Vidofludimus has produced encouraging, positive Phase IIa results in the ENTRANCE study in patients suffering from inflammatory bowel disease. Together with the developing scientific framework regarding vidofludimus' mechanism of action and influence in the modulation of cytokine expression, we believe that our novel, oral agent has the potential to become an important small molecule therapy for inflammatory bowel disease and other autoimmune diseases. We are currently anticipating the results for vidofludimus from the Phase IIb COMPONENT trial in rheumatoid arthritis which will be reported in this quarter.'

Details of the Presentations:

#1021714: 'Inhibition of IL-17 Release by the Novel Anti-Inflammatory Drug Vidofludimus Involves Attenuation of STAT3 and NF-kappa B Signaling Pathways in Murine Splenocytes and Hapten-Induced Colitis' Session date and time: May 10, 2011 from 8:00 AM to 5:00 PM Session title: IBD: Cytokines, Signaling and Receptors Session type: Poster Session Presenter: Leo R. Fitzpatrick1, Jeffrey S. Small1, Aldo Ammendola2 1Pharmacology, Penn State College of Medicine, Hershey, PA, USA; 24SC AG, Planegg-Martinsried, Germany

#1034088: 'Efficacy, Safety and Tolerability of Vidofludimus in Patients with Inflammatory Bowel Disease:

the ENTRANCE Study' Session date and time: May 9, 2011 from 8:00 AM to 5:00 PM Session title: IBD: Uncontrolled Clinical Observations Session type: Poster Session Presenter: K.R. Herrlinger1, M. Diculescu2, K. Fellermann3, H. Hartmann4, S. Howaldt5, R. Nikolov6, A. Petrov7, W. Reindl8, J.M. Otte9, S. Stoynov10, U. Strauch11, A. Sturm12, R. Voiosu13, A. Ammendola14, B. Dietrich14, B. Hentsch14, E.F. Stange1 1

Robert-Bosch-Hospital, Department of Gastroenterology, Hepatology and Endocrinology, Stuttgart, GERMANY; 2Elias University Emergency Hospital, Bucharest, ROMANIA; 3University of Schleswig-Holstein, Campus Lübeck, Lübeck, GERMANY; 4Gastroenterologische Gemeinschafts¬praxis, Herne, GERMANY; 5Gastroenterologische Schwerpunktpraxis, Hamburg, GERMANY; 6MHAT Sv Ivan Rilski, Sofia, BULGARIA; 7MHAT Tokuda Hospital Sofia, Sofia, BULGARIA; 8Technical University Munich, Munich, GERMANY; 9University of Bochum, St. Josef-Hospital, Bochum, GERMANY; 10MHAT Tsaritsa Ioanna, Sofia, BULGARIA; 11University Hospital Regensburg, Medical Clinic I, Regensburg, GERMANY; 12University Hospital Charité, Campus Virchow, Berlin, GERMANY; 13Colentina Clinical Hospital, Bucharest, ROMANIA; 144SC AG, Planegg-Martinsried, GERMANY

Copies of the presentations are available on the 4SC website under: http://www.4sc.de/product-pipeline/publications-posters.

Notes to Editor:

About Vidofludimus

Vidofludimus (4SC-101) is a novel, orally administered small molecule for the treatment of autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease. The therapeutic efficacy of vidofludimus is based on a dual principle. Vidofludimus inhibits the expression of interleukin-17 (IL-17A and IL-17F), a pro-inflammatory cytokine that has a crucial pathogenic role in a variety of autoimmune diseases. Vidofludimus also inhibits dihydroorotate dehydrogenase (DHODH), a key enzyme of the pyrimidine biosynthesis, thereby halting the proliferation of activated T and B cells which are involved in the pathology of autoimmune disorders. The combination of two mechanisms of action provides an innovative therapeutic approach with broad clinical potential in various autoimmune diseases.

About Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the gastrointestinal tract. The main forms are Crohn's disease (CD) and ulcerative colitis (UC). These chronic diseases are constituted by acute-disease flare ups which include abdominal pain, rectal bleeding, diarrhoea, weight loss, fatigue and other extra-intestinal symptoms and symptom-free phases. It is assumed that a deregulated immune response results in inflammatory mediators that attack the patient's intestinal mucosa and trigger the symptoms. For both, CD and UC, the pro-inflammatory cytokine IL-17 has been demonstrated to play a crucial role in pathogenesis. CD is characterised by an inflammatory affliction of part or the whole of the digestive tract and is currently incurable. Approximately 0.9 million people in the seven major industries suffer from various CD symptoms and mostly contract the disease between the ages of 20 and 40. CD leads to a considerable reduction in quality of life, but may also involve severe complications requiring immediate surgery. Current therapeutic options for patients are largely limited to the use of anti-inflammatory corticosteroids or immunosuppressants applied either systemically or locally for the treatment of the symptoms, as well as the application of biological agents (e.g. TNF-alpha targeting antibodies). UC afflicts specifically the large intestine or colon that includes characteristic ulcers or open sores. UC occurs in approximately 1.4 million patients in the seven major industries and is currently treated with anti-inflammatory drugs, immunosuppressants and biological agents targeting specific components of the immune response. Colectomy (partial or total removal of the large bowel through surgery) is occasionally necessary and is considered to be a cure for the disease.

About 4SC

4SC AG (ISIN DE0005753818) discovers and develops targeted small molecules for autoimmune and cancer indications. Vidofludimus (4SC-101), an oral IL-17 and DHODH inhibitor, is currently in Phase II development in rheumatoid arthritis and inflammatory bowel disease (IBD), for which positive results from a Phase IIa study were recently reported. The company's lead oncology compound, resminostat (4SC-201), an oral pan-histone deacetylase (HDAC) inhibitor, is in Phase II trials in hepatocellular carcinoma (the most common form of liver cancer), Hodgkin's lymphoma and KRAS-mutant colorectal cancer. 4SC has further oncology products in Phase I development, including 4SC-202, 4SC-203 and 4SC-205. 4SC develops drug candidates until proof-of-concept in order to generate value creating partnerships with the pharmaceutical industry in return for advance and milestone payments as well as royalties. Founded in 1997, 4SC has 94 employees and has been listed on the Prime Standard of the Frankfurt Stock Exchange since December 2005.

For further information, please visit www.4sc.com

Legal Note

This document may contain projections or estimates relating to plans and objectives relating to our future operations, products, or services; future financial results; or assumptions underlying or relating to any such statements; each of which constitutes a forward-looking statement subject to risks and uncertainties, many of which are beyond our control. Actual results could differ materially, depending on a number of factors.

 

Contact: 4SC AG
Yvonne Alexander
Investor & Public Relations
Tel.: +49 (0) 89 70 07 63 66
or
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Raimund Gabriel
Tel.: +49 (0) 89 21 02 28 30
or
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Chad Rubin
Tel.: +1 646 378 2947

 

Posted: May 2011

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