Pipex Pharmaceuticals, Inc. (AMEX: PP), a specialty pharmaceutical company developing innovative late-stage drug candidates for the treatment of central nervous system and autoimmune diseases, today announced that it has acquired an oral, once-daily candidate for the treatment of rheumatoid arthritis (RA) which has completed a 160 patient, multi-center, double-blind, randomized, placebo-controlled Phase II clinical trial for the treatment of rheumatoid arthritis (RA). Rheumatoid arthritis is an autoimmune disease which affects approximately 20 million people worldwide.

Oral dnaJP1 has been developed using computer-aided, rational drug design techniques which resulted in a short synthetic peptide derived from a heat shock protein dnaJ. Heat shock proteins and dnaJ are upregulated during cellular stress, including inflammation and autoimmune diseases. Heat shock protein responses have been found in several other autoimmune diseases other than RA, including Juvenile idiopathic arthritis (JIA), multiple sclerosis (MS) and inflammatory bowel disease (IBD). The mechanism of action of dnaJP1 relies on selectively inducing an immune shift of a T-cell function from inflammatory to regulatory, thus inhibiting disease-related inflammation and inducing a tolerogenic immunologic response. Oral dnaJP1 is a new chemical entity (NCE) which is covered by issued U.S. and international patent filings including composition of matter and methods of use patents. This phase II clinical program was supported by a million grant from the National Institutes of Health (NIH).

Below is a summary of the response data from the phase II clinical trial for oral dnaJP1 at the ACR20 endpoint along with the percentage of ACR20 response at day 112, 140 and 168 as well as day 112, 140 and 168 and day 196 follow-up without further drug therapy. ACR20 is a composite endpoint developed by the American College of Rheumatology and generally accepted as an FDA approvable scoring criteria.

Consistent with the disease modifying process of active immune tolerization, there was a progressive separation between treatment and placebo groups for both ACR20 and ACR50 endpoints after day 112. Oral dnaJP1 treated patients achieved a 40.7% ACR20 response at follow up versus 21.5% of placebo-treated patients (CMH test p=0.007, GEE p < 0.001). The proportion of dnaJP1-treated patients who achieved an ACR20 response at Days 112, 140, 168, and follow up was significantly higher than that of placebo-treated patients (CMH p=0.03; GEE p=0.0005). A statistically significant difference was also seen for the AUC when more strict ACR50 criteria are applied (GEE p-value=0.02). The primary endpoint (AUC 112-140-168) found more patients succeeding on dnaJP1 (p=0.09 by CMH and p=0.04 by adjusted GEE). GEE analysis was employed to correct for intercenter variability and this was possible as randomization occurred per center. Patients in this study were permitted to be on currently available standard background therapies, including HCQ, corticosteroids, sulfasalazine, analgesics, NSAIDS, but not on disease modifying agents or biologics.

From an immunologic standpoint, oral dnaJP1 also demonstrated an 80% reduction in the production in-vitro of TNF-alpha by T cells (p < 0.007), a hallmark cytokine of inflammation. Additionally, oral dnaJP1 treated patients demonstrated an increase in tolerogenic cytokines and immune response genes, including IL-10 and FoxP3 production.

In combination with low dose etanercept (Enbrel®), an animal equivalent of dnaJP1 has also demonstrated a significant reduction of mean arthritis scores was achieved on day 23 (p=0.0004) as compared to placebo in preclinical animal models. Additionally, oral dnaJP1 and single low dose Etanercept combination therapy led to a significant improvement of the histological score in the joints (p=0.014 vs. untreated). Lastly, combination therapy of etanercept and oral dnaJP1 led to an antigen specific increase of tolerogenic cytokines, including IL-10 and IL-4 production and up regulation of CTLA-4 expression.

Dr. Salvatore Albani, Chairman of the Arizona Arthritis Center at the University of Arizona and inventor of this program, commented, "Due to its oral activity and plausible long term durable response rate seen in RA patients in the initial multi-center, placebo controlled Phase II clinical trial, oral dnaJP1 may have an important clinical advantage over current injectable RA treatments which have significant toxicities. Our preliminary studies also strongly suggest that the mechanism of action of dnaJP1 is complementary to current biologics, thus providing the opportunity to develop combination therapies which may improve currently used regimens. The long term statistically significant improvement in clinical scores as seen by ACR20 and ACR50 following cessation of drug therapy further suggests that this technology may be inducing a tolerogenic response."

Nicholas Stergis, Pipex's Chief Executive Officer, stated, "We are pleased to have broadened our therapeutic pipeline of products with the acquisition of this innovative program. Oral dnaJP1 certainly complements our existing clinical stage immunology programs which include TRIMESTA, our oral phase II/III clinical program in multiple sclerosis and our CD4 inhibitor technology. We have been equally impressed with the rigor and quality of the scientific data, along with the level of grant funding this program has received over the years from the NIH. We look forward to reporting additional clinical data from this study later this year."

About Oral dnaJP1

Oral dnaJP1 is a once-daily epitope specific immunotherapy for rheumatoid arthritis (RA) patients. Oral dnaJP1 is a heat shock protein (hsp)-derived peptide which was previously identified as a contributor of T cell mediated inflammation in RA. Immune responses to hsp are often found at sites of inflammation and have an initially amplifying effect that needs to be downregulated to prevent tissue damage. The mechanisms for this regulation involve T cells with regulatory function that are specific for hsp-derived antigens. This regulatory function is one of the key components of a "molecular dimmer" whose physiologic function is to modulate inflammation independently from its trigger. This function is impaired in autoimmunity and could be restored for therapeutic purposes.

Oral dnaJP1 contains the five amino acid cassette present on most of the HLA class II alleles associated with RA. In preclinical work, the most relevant epitope was mapped and showed its contribution to pro-inflammatory T cell responses in vitro in patients with active RA. These data led to the hypothesis that the sequences shared between immunologically relevant self and foreign proteins (HLA and hsp) would affect thymic selection and peripheral activation of potentially pathogenic T cells at different stages (multistep molecular mimicry hypothesis, Nature Medicine 1995).

The mechanistic hypothesis is that mucosal tolerization to dnaJP1 could determine immune tolerization primarily of T cells and secondarily of APC. The effects of immune tolerance are initially peptide-specific but affect secondarily non-epitope specific pathways. Immune tolerance could translate into clinical benefit. The phase II clinical trial enrolled 160 patients with RA in 11 centers nationwide, including University of California, San Diego (UCSD), Standard University, Mayo Clinic, Virginia Mason University, Instituto Mexico, Del Serguo, University of Arizona, John Hopkins University and University of California, Irvine. Patients in the oral dnaJP1 arm of the trial received 25 mg of oral dnaJP1 daily for six months with a one month follow up.

Through a majority-owned subsidiary, Pipex has an exclusive worldwide license to issued U.S. patents and pending international patents relating to composition of matter, along with methods of use.