arGentis Acquires Rights to Rheumatoid Arthritis Therapy Entering Phase I Clinical Trial
Business Wire, Nov 12, 2009
First Clinical Trial of Orally-Administered Altered Peptide Ligand
Therapeutic
MEMPHIS, Tenn. — arGentis
Pharmaceuticals, LLC today announced that it will collaborate with
the University of Tennessee Health Science Center (UTHSC) and the
Veterans Affairs Medical Center of Memphis (VAMC) to initiate the first
human clinical evaluation of an oral altered peptide ligand (APL),
ARG301, in a Phase I study of Rheumatoid Arthritis patients. ARG301 is a
synthetic peptide, which in animal studies appears to down regulate
autoimmunity to Type II collagen (CII), a known autoantigen in RA.
Investigators at the UTHSC and Memphis VAMC developed the therapy and
have received a Clinical Merit Review Grant from the Department of
Veterans Affairs to conduct the trial.
Due to its unique mechanism of action and compelling preclinical data,
we are hopeful that ARG301 will offer a novel therapeutic approach for
rheumatoid arthritis, said Tom I. Davis, II, Chief Executive Officer of
arGentis. In continuing our partnership with UTHSC and University of
Tennessee Research Foundation, arGentis is very pleased to add this
promising oral therapeutic consistent with our autoimmunity R&D;
approach.
Research in animal models suggests APLs (Altered Peptide Ligands) are
effective in preventing and ameliorating tissue-specific autoimmune
diseases. Trials of APLs administered intravenously or subcutaneously in
human autoimmune disease have had mixed results. None of these trials,
however, incorporated a pre-selection step to test the ability in
vitro of the APL, to down regulate Th1 response by patients
bariatric weight loss peripheral blood mononuclear cells (PBMC) stimulated by a
disease-specific autoantigen such as CII in RA patients.
In preclinical testing, mice susceptible to Collagen Induced Arthritis
(CIA) bear a transgene for the human RA MHC susceptibility genes, DR1 or
DR4. These mice appear to be resistant to CIA after oral administration
of ARG301. Although the precise mechanism by which the specific peptide
comprising ARG301 exerts its effect is not yet clear, the interaction of
the APL/MHC complex with the TCR appears to play a key role in
influencing the differentiation of naive T cells into effector cells.
Based on the experience in animals, oral administration of APLs to
preselected in vitro responders should provide a nontoxic and highly
defined therapy for humans with tissue-specific autoimmune diseases such
as RA.
42 RA patients will be enrolled a Phase I Trial at the Memphis VAMC
which will evaluate multiple ascending doses of ARG301 to be
administered orally. The primary objectives of the trial will be to
determine if one or more of the three doses of ARG301 given to
Rheumatoid Arthritis patients will generate functional T regulatory
cells and decrease immune reactivity to CII. The study will have 3
ARG301 treatment arms, each with 10 patients and a placebo arm of 12
patients. Patients will be enrolled who have demonstrated T cell
immunity to CII and have an in vitro response to ARG301 at the
screening visit. Patients will be randomized to one of the 4 arms, and
each of the 3 ARG301 and placebo treatments will be given for 16 weeks.
About ARG301
The altered peptide ligand ARG301 is an oligopeptide derived from human
CII sequence with substituted amino acids that binds to the MHC class II
and interacts with the T cell receptor. ARG301 acts to change the
cytokine profile from Th1 to Th2. Preclinically, DR1 or DR4 transgenic
mice treated with oral or parenterally administered ARG301 were
protected from arthritis induced by CII immunization. Short term
toxicity studies using 100x the maximal human dose of ARG301 on a weight
basis in mice did not cause any detectable toxicity. ARG301 is
anticipated to have an exceptionally good safety profile in the clinic.
To prove concept, ARG301 will eventually be evaluated in a broader trial
of Rheumatoid Arthritis patients.
About Rheumatoid Arthritis
Rheumatoid Arthritis (RA) is an autoimmune disease that causes chronic
inflammation of the joints and is the most common form of inflammatory
arthritis. RA most often affects the smaller joints, such as those of
the hands and/or feet, wrists, elbows, knees, and/or ankles. The cause
of RA is not known but usually develops between 30 and 50 years of age
Nov 13, 2009
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