Celsus News


Celsus Reports New Validation of its Heparin Sodium USP

Cincinnati, Ohio - October 23, 2009 - Celsus Laboratories, Inc. recently completed validation of a bulk-lyophilized Heparin Sodium manufactured to specifications of the new United States Pharmacopeia (USP) monograph for heparin, effective October 1, 2009. The change includes a new USP reference standard that is used to determine the anti-Factor IIa potency of heparin and introduces new test methods for certain impurities that may be present in heparin. The monograph change will also harmonize the USP unit dose with the WHO International Standard (IS) unit dose.

FDA acknowledges Celsus' contribution to development of an analytical method for heparin

Cincinnati, Ohio - June 15, 2009 -- Celsus Laboratories, Inc. was recently recognized by FDA investigators (J. Pharm. Biomed. Anal. 2009; 49:670-673) for its contribution to the analysis for contaminants and impurities in heparin sodium using strong anion exchange high performance liquid chromatography (SAX-HPLC). Celsus announced its development of SAX-HPLC for the quantitative analysis of oversulfated chondroitin sulfate in heparin sodium in an earlier press release.

SAX-HPLC also has demonstrated to be a valuable tool in the composition and structural analysis of Celsus' enoxaparin sodium. Heparin lyase digestion of enoxaparin sodium, manufactured by Celsus pursuant to drug master file 11789, yielded di- and oligosaccharide profiles including fragments with a blocked reducing end bearing the 1,6-anhydro bicyclized ring structure that are virtually indistinguishable from the enoxaparin sodium in Lovenox® of Sanofi-Aventis.

FDA seizes OSCS-contaminated heparin from Celsus

Cincinnati, Ohio -- November 6, 2008 - Twelve lots of bulk-lyophilized heparin sodium and heparin lithium, under quarantine at Celsus since April 2008, were seized today pursuant to an FDA initiated court-ordered action. Bulk-lyophilized heparins manufactured by Celsus Laboratories for more than 20 years are intended only for research, for further manufacture into finished drug products by pharmaceutical manufacturers or for use as a component in the device industry. Celsus neither offers, distributes, nor recommends its products for retail sale or for use directly by patients.

On March 6, 2008 the FDA disclosed on its web site the potential presence of an extraneous polyanion in imported raw heparin (later determined to be oversulfated chondroitin sulfate (OSCS)) and recommended at that time the use of specialized procedures for its detection. Within days of the announcement, Celsus had put into place these procedures and opened an investigation under protocol to ascertain whether the integrity of its heparin had been affected. Suspect heparin batches were identified and quarantined. Customers, that had received heparin from such batches, were informed in late March and early April. Subsequently, having received notice as a result of the customer contacts, the FDA initiated a fact finding inspection of Celsus' Cincinnati facility from April 15 through May 15, 2008. The suspect lot numbers, their quantities and all of Celsus' consignees were disclosed to FDA investigators at that time. The quarantined lots were inspected by the agency, reconciled against company records, and re-inspected by the FDA on May 30th, June 4th and again on September 24th. On November 6, 2008 these lots under number PH-62707, PH-62807, PH-62907, PH-63507, PH- 64107, PH-64507 and HL-31707, HL-31807, HL-32708, HL-32808, HL-32908 and HL-33008, held in quarantine, were seized by United States Marshals under court order filed by the agency.

Since April 2008, a number of safeguards have been in place that prevent OSCS and other impurities from entering the supply chain of finished heparins. Imported heparin raw materials are first tested by the FDA before their release. The same raw materials are again tested by Celsus for OSCS and other impurities before their use in manufacturing. Additionally, Celsus performs all of the tests pursuant to the USP monograph on Heparin Sodium. Heparin Lithium is derived from heparin sodium and is also subject to the current impurity tests for OSCS.

Celsus and Biomat Join Forces In Europe

Cincinnati, Ohio - May 12, 2008 -- Celsus, Inc., the parent company of Celsus Laboratories, Inc. of Cincinnati, Ohio (www.heparin.com) and Dr. Ir. Leo H. Koole and Dr. Yvette B. J. Aldenhoff of the University of Maastricht have established a joint venture for the development, manufacture, and testing of bioactive polymers. The joint venture company will be named Celsus - Biomat B.V. and will be located in Geleen, the Netherlands.

Celsus-Biomat's first step will be to complete the installation of a laboratory facility at Chemelot in Geleen to formulate both Biomat's hydrophilic coating and Celsus' bioactive coating solutions for distribution in Europe. As part of their future collaboration, Celsus - Biomat will be licensed a proprietary antithrombotic agent for use as a bioactive component in drug eluting stents and other medical devices. Celsus' founder and president Cees "Case" L. van Gorp, a native of Tilburg, the Netherlands, who has spent the past 45 years abroad, said "a joint venture in Limburg will provide our European customers with an additional source of product and service". "I am especially pleased to be associated with Drs. Koole and Aldenhoff, who both are extensively published and have made significant contributions to the development of biomaterials".

Celsus, Inc., a closely-held enterprise founded in 1987, operates a FDA-registered drug establishment in Cincinnati for the development and manufacture of various crude heparin-derived active pharmaceutical ingredients (APIs). In support of its global strategy, Celsus maintains drug master file credentials with regulatory authorities in Australia, Canada, the European Union, Japan, and the United States. Celsus' pipeline of new APIs includes (i) Enoxaparin Sodium, a biosimilar version of the API in Sanofi-Aventis' blockbuster injectable drug, Lovenox® / Clexane®, and (ii) Dermatan 4,6-O-disulfate, tradenamed Intimatan™, a proprietary heparin cofactor II agonist, that is unique in its ability to inhibit surface-bound thrombin and platelet activation in the presence of heparin-induced thrombocytopenia (HIT) antibodies, both life-threatening medical conditions where heparin is counterindicated.

Biomat B.V., until recently, the Center for Biomaterials Research of the University of Maastricht, has focused its past research and development activities in the field of new biomaterials and laboratory testing thereof. Biomat's expertise includes hemocompatibility testing, the manufacture of methacrylate-based hydrophilic coatings, and the synthesis of various fluorogenic and chromogenic substrates designed for the determination of antiprotease activities.

Benzalkonium Heparin Now Available Directly From Celsus Laboratories

Cincinnati, Ohio - May 6, 2008 -- Celsus Laboratories, the leading manufacturer of subject product, announces a change in its distribution of Heparin Benzalkonium solution, also known as H-Bac, intended for use as a bioactive coating of catheters, and guidewires. Celsus found it problematic from a quality system point of view of having an intervening party between the product and the manufacturers of medical devices. Therefore, the Celsus product will no longer be available from NAMSA.

The change only impacts those device manufacturers that have sourced Benzalkonium Heparin Solution or H-Bac from NAMSA or its distributors. Such manufacturers are invited to purchase any future requirements directly from Celsus Laboratories. Benzalkonium heparin solution is being dispatched under UN-rated conditions from inventory in 1 liter or 16 liter quantities. Orders may be placed either by email or by faxing +1 (513) -772-8132.

Both Benzalkonium Heparin (HB-3185) and Benzalkonium Heparin Solution (BY- 3189) are derivatives of Heparin Sodium of porcine tissue manufactured by Celsus Laboratories pursuant to drug master files reviewed by regulatory authorities in Australia, Canada, the European Union, Japan and the United States.

Celsus Laboratories Discloses Its SAX-HPLC Test For Heparin Sodium

Cincinnati OH - April 16, 2008 - - In light of the recent concern about contaminated heparin, Celsus Laboratories is offering for consideration by regulatory agencies and industry, strong anion exchange high performance liquid chromatography (SAXHPLC) as an alternative method for the quantitative analysis of heparin-like glycosaminoglycans in Heparin Sodium USP.

The method, developed by Celsus, is rapid, quantitative, and exhibits high resolution for the discrimination and identification of not only the naturally-occurring glycosaminoglycans, but also oversulfated chondroitin sulfate (OCS). Analysis time is typically 30 minutes from injection. It further offers the advantage that HPLC is available to many more laboratories than 500 MHz nuclear magnetic resonance (NMR) spectroscopy and Capillary Electrophoresis (CE), the current methods of analysis. Presently lacking, unfortunately, is a readily available reference standard. Nonetheless, even without a standard, SAX-HPLC is a high resolution method for quickly determining the quantity of OCS-like species in Heparin Sodium USP and commercial heparin preparations derived thereof.

Celsus Laboratories, Inc., located in Cincinnati, Ohio, has been active as a FDAinspected manufacturer and global distributor of bulk-lyophilized derivatives of crude heparin since 1988.

Celsus First to Manufacture Commercial Quantities of Generic Enoxaparin Sodium in the U.S.

Cincinnati, Ohio - August 8, 2007 -- In anticipation of a generic market, Celsus Laboratories has positioned itself to be the first manufacturer of Enoxaparin Sodium in the U.S. Enoxaparin Sodium is a low molecular weight heparin (LMWH) manufactured and offered by Celsus as an alternative to the active pharmaceutical ingredient (API) in the listed drug Enoxaparin Sodium Injection, the anticoagulant of choice for the treatment and prevention of venous thrombosis.

Venous thrombosis is the third most common cardiovascular disorder, affecting about two million people each year in the US alone. Of these, around 60,000 will develop a pulmonary embolism which will prove fatal in 8-10% of cases. Venous thromboses is commonly treated with heparin sodium, or the low molecular weight heparins (LMWHs), or a synthetic alternative known as fondaparinux. The most commonly prescribed LMWH in the Americas and Europe is Sanofi-Aventis' Lovenox® / Clexane® (enoxaparin sodium) with worldwide sales in 2006 of more than $ 3 billion of which almost $ 2 billion was in the US alone. The large U.S. share of the global market is due to a significantly higher price in the U.S. than in the rest of the world. Not surprisingly, a number of companies are anxiously awaiting a decision on an appeal filed by Sanofi-Aventis to reverse a lower court decision of unenforceability of its LMWH patent due to inequitable conduct in its prosecution of the patent. ANDA applications for a generic enoxaparin have been filed in the U.S. by Amphastar, Teva, and Momenta. The first two procure their API from foreign sources. The latter licensed the manufacture of commercial quantities of its API to Sandoz of Germany.

Celsus to Commence Phase I Clinical Studies of Intimatan™

CINCINNATI, Ohio -- January, 2007-- Celsus, Inc. announced plans to initiate phase I clinical studies of Intimatan™ while considering out-licensing opportunities for the major pharmaceutical markets.

Intimatan™ is an improved anti-inflammatory anticoagulant intended for use in indications dominated by heparin. Among its competitive advantages as a heparincofactor II agonist, Intimatan: (i) inhibits both systemic and clot-bound thrombin, the latter resistant to inhibition by the heparin-antithrombin complex; (ii) imparts an improved therapeutic index as demonstrated in high hurdle models of venous and arterial thrombosis; (iii) restores anticoagulant activity in antithrombin-deficient plasma of patients with both hereditary and acquired heparin resistance; (iv) blocks platelet activation in plasma of patients with heparin-induced thrombocytopenia (HIT) or "white clot syndrome", making Intimatan the first-in-class HIT-antagonist that abates the heparin-induced disease mechanism at its immunological root cause while affording anticoagulant and antithrombotic protection, and (v) reduces infarct size due to ischemia-reperfusion injury. In adjuvant settings, Intimatan shows synergy with glycoprotein IIb/IIIa inhibitors to yield complete myocardial protection in coronary arterial thrombosis models at signficantly reduced doses that diminish hemorrhagic effects, and prevents rethrombosis following successful fibrinolysis with recombinant tissue plasminogen activator. Protamine is an effective antidote for Intimatan as well as unfractionated heparin. There are no specific antidotes for low molecular weight heparin or the direct thrombin inhibitors, hirudin, lepirudin, bivalirudin and argatroban.

European Patent Office Grants Celsus Patent For Intimatan

Cincinnati OH - June 23, 2005 -- Celsus, Inc. announced today that the European Patent Office has granted the company EP 0 983 304 B1 for dermatan disulfate, an inhibitor of thrombin generation and complement activation. With the European Patent Office process completed and the patent granted, Celsus is now seeking "nationalization" of the patent in the major countries of the European Union.

In contrast to heparin and low molecular weight heparin (LMWH), the current anticoagulants of choice, (i) dermatan disulfate, also known as Intimatan™, catalyzes heparin cofactor II-dependent inhibition of both soluble and surface-bound thrombin, thus suppressing the thrombin feedback loop, at doses that pose minimal systemic anticoagulation or bleeding, and (ii) in animal models, Intimatan has shown to be more effective as an inhibitor of venous and arterial thrombisis, to prevent recurrent arterial thrombosis after successul thrombolysis with tissue plasminogen activator and to act synergistically with glycoprotein IIb/IIIa receptor antagonists to inhibit human platelet activation. These properties may position Intimatan™ as a preferred anticoagulant for use in acute thrombosis indications, especially for antithrombin III-deficient patients.

Recent studies have shown that Intimatan™ inhibits the activation of human platelets induced by heparin when incubated with immune serum from patients with heparin-induced thrombocytopenia (HIT), thereby qualifying Intimatan as the first anticoagulant HIT-antagonist. HIT, previously known as white clot syndrome, is a debilitating disease that affects 2 - 5% of the 12 million patients in the U.S. on heparin and LMWH therapy.

Celsus Qualifies for a Third NIH Grant for Drug Development

02/28/03 -- Celsus Laboratories, Inc. (Cincinnati OH) announces it received a $224,000 phase I research grant from the National Heart, Lung, and Blood Institute for a preclinical study of the drug, Intimatan. Included will be research in a revascularization model of ischemic reperfusion injury during cardiopulmonary bypass (CPB) surgery by Emory University. The new study is designed to further test the efficacy of Intimatan as a replacement for heparin in cardiac surgery.

Intimatan is a patented heparin cofactor II agonist, comprising a disaccharide sequence of repeating L-iduronic acid N-acetyl-D-galactosamine 4,6-O-disulfate joined by 1,3 and 1,4 linkages. This naturally-occurring, but rare, disaccharide may be prepared by synthesis or by site-selective 6-O-sulfation of native dermatan sulfate.

Current practice for CPB surgery requires high dose heparin (400 U/kg) to maintain patency of the extracorporeal circuits during flow. However, thrombin bound to the fibrin clot, vessel wall and biomaterial surfaces is typically resistant to inhibition by heparin. In comparison with heparin, using a pig model of CPB, Intimatan maintained extracorporeal patency at one tenth the anticoagulant dose; generated a 4-fold lower activated clotting time (ACT); reduced chest wall bleeding more than 2- fold; and did not induce thrombin rebound or require neutralization post-procedure. In contrast, the use of heparin requires post surgical neutralization which often results in heparin-protamine-complex-induced complement activation contributing to post-operative edema, tissue injury and neural deficits.

Other preclinical pharmacology studies, thus far, have shown Intimatan to be an inhibitor of surface-bound thrombin, complement activation, and neointimal hyperplasia in models of restenosis injury. In the treatment of acute coronary thrombosis, Intimatan reduces the dose of platelet GPIIb/IIIa inhibitors required to block coronary thrombosis in vivo and prevents recurrent coronary artery thrombosis in the canine following adjuvant thrombolysis with tissue plasminogen activator. It completely prevents primary arterial and venous thromboses in the canine model of electrolytic injury. Intimatan also protects against inflammation damage to the isolated perfused rabbit heart and may thus protect against the ravages of ischemicreperfusion injury in myocardial infarction and stroke. Furthermore, Intimatan blocks the activation of platelets of patients with heparin-induced thrombocytopenia (HIT) caused by heparin allergy. As a HIT antagonist, Intimatan may benefit highrisk cardiac patients who experience thrombosis due to heparin exposure.

Combination of Glycoprotein IIb/IIIa Platelet Receptor Antagonist and Heparin Cofactor II Agonist receives Notice of Patent Allowance.

10/02/02 -- Intimax Corporation (Cincinnati OH), a subsidiary of Celsus, Inc., received from the USPTO a notice of allowance for a patent claiming combination of glycoprotein (GP) IIb/IIIa platelet receptor antagonist and heparin cofactor II agonist for use in the treatment of thrombo-embolic disorders arising from platelet- and thrombin-dependent-coagulation processes. Treatment typically addresses the inhibition of platelet aggregation and thrombin generation and activation by use of a GP IIb/IIIa antagonist in combination with various anticoagulants including heparin.

A variety of animal pharmacology studies have shown Intimatan, a heparin cofactor II agonist under development at Celsus, to be a superior anticoagulant to both unfractionated and the low molecular weight heparins in cardiac surgery and in the treatment of thrombosis. In contrast to the heparins, Intimatan blocks both thrombin generation and thrombin activity via a sustained action at the vessel wall that suppresses the thrombin feedback loop, at doses that pose minimal systemic anticoagulation or bleeding. In the patented combination Intimatan has been shown to act synergistically with GPIIb/IIIa antagonists, at sub-therapeutic doses of both, to maintain vessel patency with less bleeding than GPIIb/IIIa antagonists in combination with the heparins. Intimatan also ameliorates the activation of human platelets induced by immune serum of patients with heparin induced thrombocytopenia (HIT). These properties potentially make Intimatan the preferred anticoagulant adjuvant for the treatment of acute myocardial infarction with fibrinolytic agents and GPIIb/IIIa antagonists and/or peri- and post-surgery in the cardiac patient.

Celsus Receives Research Funding To Develop O-Desulfated Heparin

9/3/02 - Celsus Laboratories, Inc. received a phase I Small Business Innovation Research (SBIR) grant from the U.S. Department of Health and Human Services to develop a process for the manufacture of an O-desulfated heparin the use of which has been shown experimentally to prevent ischemic reperfusion injury such as that associated with myocardial infarction, stroke and pulmonary thromboembolism. The research will be done in collaboration with the Carolinas Medical Center of Charlotte NC.

Intimatan™ Prevents Rethrombosis After Successful Thrombolysis

8/12/02 - Celsus Laboratories, Inc. and investigators of the University of Michigan will present the results of a study of Intimatan in the presence and absence of an adjuvant thrombolytic agent in a canine model of deep vessel wall injury on September September 10th 2002 at the 17th Congress of the International Fibrinogen Research Society in Munich Germany.

Intimatan (9 mg/kg plus an infusion of 300 μg/kg/min, i.v.) significantly increased the time to carotid artery (CA) (226 ± 0.4 min) and jugular vein (JV) (240 ± 0.0 min) thrombosis compared with control vessels in the same animal (87.1 ± 7.9 CA and 60.0 ± 7.4 min JV) determined before drug administration. Vessel patency was maintained in 8/8 JV and 7/8 CA during Intimatan treatment. Although dalteparin (400 IU/kg, s.c.) delayed the time to thrombosis in the CA (122 ± 17.5) relative to control CA (64.3 ± 8.2), it had no effect on the time to thrombosis in the JV, whereas only one CA remained patent at the end of the 240 min protocol. After establishing successful thrombolysis with recombinant tissue plasminogen activitator (rt-PA), Intimatan decreased the incidence of rethrombosis in the right CA to 1/7 versus 4/7 in the vehicle-treated groups. After thrombolysis, the quality of right CA blood flow assessed by the patency score (scale 0-3) was 2.6 ± 0.4 for Intimatan and 1.1 ± 0.6 for vehicle control. In the left CA, the incidence of occlusion was 0/7 (Intimatan) versus 2/7 (vehicle control) and the patency score was 2.7 ± 0.6 (Intimatan) vs 1.6 ± 0.5 (vehicle) after thrombolysis. The results demonstrate that Intimatan prevents occlusive arterial and venous thrombosis in an experimental model of deep vessel wall injury and prevents CA rethrombosis after successful thrombolysis with rt-PA. These effects are achieved with minimal increases in the bleeding time and activated partial thromboplastin time. Intimatan is an improved anticoagulant and new drug candidate for the treatment of coronary syndromes in the setting of adjuvant thrombolytic therapy.