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
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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.
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