Pipex Pharmaceuticals, Inc. (AMEX: PP) (“Pipex”), a specialty pharmaceutical company developing innovative late-stage drug candidates for the treatment of neurologic and fibrotic diseases, announced clinical results of Alzheimer’s disease test using FreeBound, Pipex’s proprietary pharmacodiagnostic device for measurement of serum free and total copper.
Dr. David A. Newsome was also highlighted on a medical news segment by New Orleans CBS news affiliate, WWLTV channel 4, entitled, “Copper, drinking water and vitamins.” This segment can be viewed through Pipex’s website, www.pipexinc.com.
With the assistance of Dr. Joseph A. Quinn, Associate Professor of Neurology at the Oregon Health & Sciences University (OHSU), 52 frozen samples taken from Alzheimer’s disease patients (n=40) and age-matched controls (n=12), with an average age of 70 years were analyzed on a blinded basis for levels of serum free copper using the FreeBound diagnostic device. A seventy percent (70%) increase in free serum copper was detected in Alzheimer’s disease patients versus age-matched controls (p < 0.02). Additionally, percent free copper detected was also statistically significantly higher in AD patients than age matched controls (p < 0.018). The percent of free serum copper is the amount of free serum copper expressed as a percent of total serum copper. These samples were provided by the Oregon Alzheimer’s disease center.
The following table presents the results of the study using FreeBound:
Percent of Free Free Copper in Serum Copper in Serum (mean values, ug/dL) (mean values, ug/dL) AD Patients 16.8 11.2 Age-Matched Controls 9.9 6.6 P-values P < 0.02 P < 0.018
David A. Newsome, M.D., Chief Scientific Officer of Pipex, commented, “These highly statistically significant findings confirm previously reported scientific results implicating the involvement of elevated levels of ‘free’ copper in the pathogenesis of Alzheimer’s disease. One possibility is that these patients present with increased ‘free’ copper is due to their dietary source of highly oxidative mineral. It is well known that many municipal tap water sources as well as dietary supplements, such as multi-vitamins which generally contain up to 2mg of free copper, can supply more copper than an elderly patient might need. FreeBound’s ability to detect unbound copper is seminal to creating therapeutic modalities for the treatment of this devastating CNS disease, as well as being able to detect other copper mediated disorders, such as Wilson’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS), autism and schizophrenia.”
Steve H. Kanzer, Chairman and Chief Executive Officer of Pipex, commented, “The purpose of this study is to build upon and confirm free copper’s involvement in Alzheimer’s disease. These results, along with our recent results using COPREXA, our lead anti-copper molecule which reduced insoluble amyloid-beta, a key AD protein by 40% (p < 0.05) in animal models, provides additional basis for further testing of this approach in this important CNS-localized disease. Our FreeBound diagnostic device should allow clinicians to pre-select patients with elevated levels of CNS copper who might benefit from copper-reduction therapy.”
John Althaus, Vice President of Advanced Technology and co-inventor of FreeBound commented, “Traditional methods to detect levels of free copper in serum are indirect, inconvenient and slow and can easily lead to inaccurate free copper values. These traditional methods may have also led to misdiagnosis and incorrect pharmacologic treatment of these patients. As a scientist, I am extremely pleased with the performance and versatile nature of our FreeBound diagnostic device and look forward to utilizing it in further clinical tests, to monitor the longitudinal effects of COPREXA therapy.”
Clinical Correlation of Copper and Alzheimer’s Disease
Over the last several years, an increasing body of evidence points to dysfunctional copper homeostasis in the pathogenesis of dementia. Most recently, a published observational six year study in 3718 patients over the age of 65, concluded that subjects that consumed a typical amount of a copper supplement (1.6mg of copper a day) when taken together with a high saturated and trans fat diet results in an equivalent of 19 years of mental decline (p < 0.001) (2).
In a separate European clinical study conducted in 53 patients, correlated the levels of the highly reactive “free copper” (also known as copper not bound to protein) pool in serum to disease severity in AD patients versus aged-matched control patients. These results demonstrated that the “free copper” serum pool was highly increased in AD patients (4).
These clinical studies are complemented by preclinical studies that show that AD amyloid-betta plaques when treated with copper chelating agents in vitro loosen and reverse fibril formation as determined by spectroscopy.
Subject to initial and necessary registration clinical trials to support its use in treating AD, COPREXA’s specificity and unique mechanism of action for lowering toxic free copper levels in the CNS, combined with its history of success in completed pivotal clinical trials of neurologically-presenting Wilson’s disease, may make it highly useful in the treatment of both the acute cognitive dysfunction (copper-mediated synaptic excitotoxicity) as well as long-term neurodegenerative aspect (copper-induced oxidation and neuronal death) of AD. COPREXA’s ability to specifically bind only toxic free copper, as opposed to increasing free copper levels by virtue of liberating bound copper, for example, amongst other properties, we believe differentiates COPREXA from other non-specific metal chelating compounds previously investigated for neurodegenerative diseases.
About FreeBound Device
Copper, an essential metal, is made available to organs throughout the body via the systemic circulation via a tightly regulated system of copper chaperones and copper transport proteins. Normally, approximately 90% or more of serum copper is tightly bound to the serum copper chaperone called ceruloplasmin (Cp). The remaining 10% of serum copper represents the so-called “free” or “non-ceruloplasmin bound” copper pool and can be highly toxic to the brain the organ which is most sensitive to the effects of free copper. In Wilson’s disease patients, the free copper pool is expanded and causes psychiatric symptoms and neurodegeneration in affected patients.
Direct and accurate measurement of this important toxic pool of free copper in serum has until now remained elusive. The current standard methodology for measuring free copper relies instead on an inexact indirect estimate involving a two step process. First, total serum copper is typically measured using an expensive and time consuming technique called atomic absorption. Second, serum Cp concentrations are determined by immunoassay or enzymatic assay. Once Cp is determined, the estimated amount of copper atoms believed to be bound to Cp is calculated and subtracted from total copper to arrive at an estimate of free copper in serum. The result is an inexact, expensive and time consuming process that carries a large potential for error based on erroneous assumptions and experimental deviations from multiple measurements.
We believe that by using the FreeBound device, free copper levels can be determined using technology similar to and as simple to use as a glucometer that incorporates electrochemical detection. Serum is applied to test strips attached to a meter. The meter is programmed to separate and measure free copper versus Cp-bound copper on the test strip immediately displaying the results on the meter.
About COPREXA
COPREXA is an oral, small-molecule, anti-copper agent that is highly specific for the reduction of free copper in serum, the most toxic form of copper in the body, and is thus ideally suited for the treatment of central nervous system (CNS) diseases in which abnormal serum and CNS copper homeostasis are implicated. COPREXA has completed pivotal clinical trials for the treatment of neurologically presenting Wilson’s Disease, an orphan disease of the CNS, and Pipex plans to file an NDA with the FDA for this indication during this month, November 2007.
Pipex is also developing COPREXA for fibrotic disorders based upon the rationale that the fibrotic disease process is dependent upon the availability of free copper in the body. COPREXA has demonstrated the ability to inhibit fibrosis in a number of well established animal models through the sequestration of available copper and inhibition of key fibrotric cytokines, including secreted protein acid rich in cysteine (SPARC), NFkappaB, TGF-betta, FGF-2, IL-1, IL-6, IL-8, and connective tissue growth factor (CTGF).
COPREXA has also completed a one year phase I/II clinical trial for the treatment of refractory Idiopathic Pulmonary Fibrosis (IPF), a deadly lung disease. Pending regulatory feedback on such a study, Pipex is planning to launch a phase III registration clinical for the treatment of IPF with COPREXA.
References and Further Reading About Copper and Alzheimer’s Disease
For further reading on the subject of free copper and Alzheimer’s disease, the following cited references may be quickly and easily accessed at www.pubmed.gov by simply entering the corresponding PubMed ID:
(1) Sparks DL, Schreurs BG, Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s
disease. PNAS 100(19):11065-9 (2003) PubMed ID: 12920183
(2) Morris et al., Dietary copper and high saturated and trans fat intakes associated with cognitive decline., Arch. Neurol 63:1085-1088; (2006) PubMed ID: 16908733
(3) Miller LM et al., Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with beta-amyloid deposits in Alzheimer’s disease. J Struct Biol 155(1):30-7 (2006) PubMed ID: 16325427
(4) Squitti et al., Excess of serum copper not related to ceruloplasmin in Alzheimer disease. Neurology 67:76-82; (2006) PubMed ID: 15781823
(5) Syme D et al., Copper binding to the amyloid-beta (Abeta) peptide associated with Alzheimer’s disease: folding, coordination geometry, pH dependence, stoichiometry, and affinity of Abeta-(1-28): insights from a range of complementary spectroscopic techniques. J Biol Chem 279(18):18169-77 (2004) PubMed ID: 14978032
(6) Ma QF et al., Binding of copper (II) ion to an Alzheimer’s tau peptide as revealed by MALDI-TOF MS, CD, and NMR. Biopolymers 79(2):74-85 (2005) PubMed ID 15986501
(7) Barnham KJ et al., Structure of the Alzheimer’s disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J Biol Chem 278(19):17401-7 (2003) PubMed ID: 12611883
(8) Angeletti B et al., BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper. J Biol Chem 280(18):17930-7 (2005) PubMed ID: 15722349
(9) MiyataM, Smith JD, Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat. Genet. 14(1):55-61 (1996) PubMed ID: 8782820
About Pipex Pharmaceuticals, Inc.
Pipex Pharmaceuticals, Inc. (“Pipex”) is a specialty pharmaceutical company that is developing proprietary, late-stage drug candidates for the treatment of neurologic and fibrotic diseases Pipex’s strategy is to exclusively in-license proprietary, clinical-stage drug candidates and complete the further clinical testing, manufacturing and regulatory requirements sufficient to seek marketing authorizations via the filing of New Drug Applications (NDAs) with the FDA in the U.S. and Marketing Application Authorizations (MAAs) with the European Medicines Evaluation Agency (EMEA).
For further information, please visit, www.pipexinc.com. This press release contains forward-looking statements, within the meaning of Section 21E of the Securities Exchange Act of 1934, that reflect Pipex Pharmaceuticals, Inc. and subsidiaries (“we” or “our”) current expectations about its future results, performance, prospects and opportunities, including statements regarding the potential use of FreeBound or its use as a diagnostic tool, COPREXA(TM) for the treatment of Alzheimer’s disease, inflammatory and fibrotic diseases, as well as the prospects for regulatory filings in the treatment of neurologic Wilson’s disease, including filing NDA with the FDA during November 2007 and that such NDA will be accepted for filing by the FDA and/or that the FDA will agree with our analysis of data supporting the safety, clinical efficacy, manufacturing, stability and other regulatory requirements necessary for COPREXA to be approved for use in neurologically presenting Wilson’s disease or that even if approved for initial indication, that we will be able to conduct and complete necessary initial and registration clinical trials required to support and receive FDA approval for a Supplemental New Drug Application to market COPREXA for the treatment of Alzheimer’s disease or other disease indications, such as, idiopathic pulmonary fibrosis, for example. Where possible, the Company has tried to identify these forward-looking statements by using words such as “anticipates,””believes,””intends,” or similar expressions. These statements are subject to a number of risks, uncertainties and other factors that could cause actual events or results in future periods to differ materially from what is expressed in, or implied by, these statements, including risks set forth in our filings with the Securities and Exchange Commission. We cannot assure you that we will be able to successfully develop or commercialize products based on our technologies, including COPREXA(TM), TRIMESTA(TM), SOLOVAX(TM), EFFIRMA(TM) or Anti-CD4 802-2, particularly in light of the significant uncertainty inherent in developing, manufacturing and conducting preclinical and clinical trials of new pharmaceuticals, and obtaining regulatory approvals, that our technologies will prove to be safe and effective, that our cash expenditures will not exceed projected levels, that we will be able to obtain future financing or funds when needed, that product development and commercialization efforts will not be reduced or discontinued due to difficulties or delays in clinical trials or due to lack of progress or positive results from research and development efforts, that we will be able to successfully obtain any further grants and awards, maintain our existing grants which are subject to performance, that we will be able to patent, register or protect our technology from challenge and products from competition or maintain or expand our license agreements with our current licensors, or that our business strategy will be successful. All forward-looking statements made in this press release are made as of the date hereof, and the Company assumes no obligation to update the forward-looking statements included in this news release whether as a result of new information, future events, or otherwise, other than as required by law.
For Further Information Contact: Steve H. Kanzer, CPA, Esq. Chairman and Chief Executive Officer (734) 332-7800 Thomas Redington, Ph.D. (investor relations) Redington, Inc. (203) 222-7399
SOURCE: Pipex Pharmaceuticals, Inc.
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