Isis Crohn's Disease Drug Shows Evidence of Durable Remission, Steroid-Sparing And Fistula Healing Effects
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Results of Phase II Trial Show Inhibition of ICAM-1 and
Other Inflammatory Markers, Supporting Antisense Mechanism
CARLSBAD, Calif., June 10 /PRNewswire/ -- In the June 1998 issue of
Gastroenterology, Isis Pharmaceuticals (NASDAQ:ISIP) and Crohn's disease
academic researchers report on the results of a well-controlled 20-patient
Phase II trial of ISIS 2302 in the treatment of Crohn's disease. These
results show a statistically significant lowering of steroid requirements
(p=0.0001) in ISIS 2302-treated patients, and show that by the end of the on-
month treatment period, ISIS 2302 produced disease remission (Crohn's Disease
Activity Index <150) in 47% of patients treated with the drug. The mean
duration of remission was prolonged; at the end of the 6-month trial, 5 of the
7 ISIS 2302-treated remitters were still in remission following a single
course of treatment. In addition, at the end of 6 months, corticosteroid
treatment was completely discontinued in 33% (5 of 15) of the ISIS 2302
treated patients and in no placebo patients. Long-term steroid use can cause
severe side effects including osteoporosis, immune suppression and
endocrinological changes.
This publication includes data on the 20-patient, double-blinded, placebo-
controlled, randomized (3:1; ISIS 2302: placebo) Phase II trial which were
previously presented at two scientific conferences, as well as data supporting
that ISIS 2302 is working through an antisense mechanism.
The publication is entitled, "A Placebo-Controlled Trial of an ICAM-1
Antisense Oligonucleotide in the Treatment of Crohn's Disease." The authors
are Bruce R. Yacyshyn, M.D., Mary Beth Bowen-Yacyshyn, Ph.D., Lawrence Jewell,
M.D., of the Department of Gastroenterology, University of Alberta, Edmonton;
Joseph A. Tami, Pharm.D., C. Frank Bennett, Ph.D., Daniel L. Kisner, M.D., and
William R. Shanahan, Jr., M.D., of Isis Pharmaceuticals.
ISIS 2302 is an antisense inhibitor of intercellular adhesion molecule -1
(ICAM-1), a cell adhesion molecule implicated in a wide range of inflammatory
diseases and conditions. The drug is a key asset in the cell adhesion
collaboration between Isis and Boehringer Ingelheim GmbH. A 300-patient
pivotal quality trial of ISIS 2302 in patients with steroid- dependent Crohn's
disease is underway in North America and Europe.
Fistulae Healing
Two patients who had an open fistula when they entered the study and were
treated with ISIS 2302 experienced healing of their fistula. Fistulae are
open channels from the bowel to the skin and other organs through which fecal
matter can drain, causing soiling, pain and infection. In addition, both
patients in this study with gastroduodenal Crohn's disease (located where the
stomach meets the intestine) were treated with ISIS 2302, and both experienced
resolution of upper gastrointestinal obstructive symptoms during the course of
treatment. These two patients remain free of their obstructive symptoms after
over one year following treatment with ISIS 2302.
"The ability of ISIS 2302 to produce durable remissions in patients with
steroid-dependent Crohn's disease, to heal fistulae and to reduce and, in many
patients, eliminate steroid use, strongly suggests that ISIS 2302 can be an
important treatment for Crohn's disease," said Bruce R. Yacyshyn, M.D.,
Division of Gastroenterology, University of Alberta, Edmonton, and lead author
on the paper.
Antisense Mechanism Supported
Newly released findings reported in the Gastroenterology article suggest a
strong correlation between treatment with ISIS 2302, reduction in ICAM-1
expression in affected bowel tissue and apparent release of proinflammatory
lymphocytes from the gut. In the intestinal mucosa of patients treated with
ISIS 2302, decreases in ICAM-1 expression (CD54) were seen in significantly
more of the ISIS 2302-treated patients than placebo-treated patients, and
higher doses of ISIS 2302 produced greater effects. In addition, an increase
in peripheral blood T-cells bearing the adhesion molecules alpha-d and beta-7,
which are involved in lymphocyte homing to the intestine, was observed. The
correlation of ICAM-1 inhibition and the apparent release of immune cells from
the intestine suggest that suppression of ICAM-1 results in an interruption of
the immune cell intestinal trafficking and retention that are critical to the
perpetuation of the inflammatory disease process. This interruption may allow
restoration of normal bowel mucosal integrity and immune function, thereby
resulting in prolonged disease suppression.
"In patients treated with ISIS 2302, the changes observed in peripheral
blood lymphocyte and intestinal mucosal expression of adhesion molecules
strongly suggest a therapeutic effect with ISIS 2302 achieved through an
antisense mechanism of action. These data provide the first evidence of an
interplay in inflammatory disease between specific cell adhesion molecules,
with potential implications for designing antiinflammatory drugs in the
future," said Dr. Yacyshyn.
This press release contains forward-looking statements concerning the
therapeutic potential of ISIS 2302, an antisense drug in development for
Crohn's disease and other inflammatory disorders. Such statements are subject
to certain risks and uncertainties, particularly those inherent in the process
of discovering, developing and commercializing drugs that are safe and
effective for use as human therapeutics. Actual results could differ
materially from those projected in this release. As a result, the reader is
cautioned not to rely on these forward-looking statements. These and other
risks concerning the therapeutic potential of ISIS 2302 are described in
additional detail in Isis' Annual Report on Form 10-K for the year ended
December 31, 1997 and in the company's most recent quarterly report on Form
10-Q, which are on file with the U.S. Securities Exchange Commission, copies
of which are available from the company.
Isis Pharmaceuticals, based in northern San Diego County, is engaged in
the discovery and development of novel human therapeutic compounds. Isis has
six compounds in human clinical trials: fomivirsen, to treat CMV-induced
retinitis in AIDS patients, has completed Phase III clinical trials and an NDA
has been filed; ISIS 2302, an inhibitor of ICAM-1, is in a pivotal quality
trial for Crohn's disease, Phase II clinical trials for renal transplant
rejection, rheumatoid arthritis and ulcerative colitis, and is being explored
as a topical administration for psoriasis and an aerosol administration for
asthma; ISIS 3521/CGP 64128A is in Phase II trials as a treatment for cancer;
ISIS 5132/CGP69846A is in Phase II clinical trials as a treatment for cancer;
ISIS 2503 is in Phase I trials as a treatment for cancer; and ISIS 13312 is in
Phase I/II clinical trials for the treatment of CMV retinitis in AIDS
patients. The company also has several additional compounds in preclinical
development. Isis' broad medicinal chemistry and biology research programs
support efforts in both antisense and combinatorial drug discovery.
SOURCE Isis Pharmaceuticals
-0- 06/10/98
/CONTACT: Jane Green, Senior Director, Investor Relations, of Isis
Pharmaceuticals, 760-603-3880/
/Web site: isip.com |
