• The Need:

Heparin reversal
Heparin is an antithrombotic (clot prevention drug), which is commonly used in certain acute surgical applications. In particular, heparin is routinely used in cardiothoracic surgical procedures, such as cardiac bypass, to prevent blood clots from forming during the surgery. These blood clots can be potentially life threatening, since they can lodge in the brain and cause a stroke, or in the heart and cause a heart attack. As a result, cardiothoracic surgery is generally done with the patient receiving high doses of heparin.

After the surgery, the heparin needs to be reversed, to allow the patient to clot and heal normally. There is currently only one agent available in the world to reverse heparin action: protamine. Though widely used, protamine has many well documented toxicities and problems, including:

• Difficulty in titrating (adjusting) dose – protamine itself has anticoagulant properties, and if administered in higher doses than needed, may worsen bleeding.
• Allergic reactions – protamine is a protein derived from fish products, and may cause allergic reactions in some patients, which, while incommon, can be life threatening.
• Immunogenicity risk – because protamine is a foreign animal protein, patients may develop an immune reaction to it. This can complicate subsequent administration of protamine for repeat procedures, in which case it may either not work, or may cause a potentially dangerous allergic (anaphylactic) reaction. Such reactions are unpredictable and greatly feared. Certain patient groups, such as diabetics taking insulin, or males that have had vasectomies, may also be at greater risk of having an immune reaction to protamine and thus experience difficulties in receiving it.
• Inhibiting normal clot formation – protamine has poor fibrokinetics, which is, it can interfere with normal clot formation. Thus, there is a risk of a recurrence of bleeding after administration of protamine.
• Lack of activity against Low Molecular Weight Heparin (LMWH). The LMWH’s are used in chronic settings, for long term management of thrombosis (to prevent the formation of potentially dangerous clots). There is a risk of bleeding with LMWH, and protamine is not generally clinically effective at reversing this effect.

Thus, we believe there is a significant medical need and attractive commercial opportunity for developing a new reversing agent for heparin, and a replacement for protamine.

LMWH reversal
Because of their superior pharmacodynamic properties compared with unfractionated heparin (easier dose titration) and routes of administration (s.c. injection instead of intravenous), Low Molecular Weight Heparins (LMWH, such as Lovenox/Sanofi Aventis; Fragmin/Pfizer and Eisai; Sandoparin/Novartis; Innohep/LEO; Fraxiparin/GSK) are widely used for chronic prevention of thrombosis, such as prevention of deep vein thrombosis (DVT), in patents that have had heart attacks (post MI, myocardial infraction), and in cancer patients. LMWH products have total annual sales of over $4 billion.

Clinical studies have shown that there is a 1%-4% rate of major bleeding episodes associated with LMWH usage, with up to a 20% overall bleeding rate in certain patient populations. Protamine is not effective in reversing LMWH activity, and no clinically effective antidote for the LMWHs has been identified. Current treatments for bleeding associated with LMWH generally consist of transfusion, hospitalization, and surgery, which can be expensive and of inconsistent effectiveness.

More recently, an anti-coagulant comprised of the pentasaccharide sequence alone has been approved for clinical use (Arixtra) but it also has no effective antidote. Therefore, we believe there is a strong medical need for safe and effective heparin, LMWH and pentasaccharide antagonists.

• The News:
PolyMedix has developed novel small molecules that act as universal anticoagulant reversing agents: active against both heparin, low molecular weight heparin (LMWH) and pentasaccharide (Arixtra); we call these compounds Heptagonists. PMX-60056 has been selected as the lead heptagonist IND clinical candidate.

We have shown that PMX-60056 and other heptagonist compounds are:

• Potent and broad spectrum, active against heparin, LMWHs and pentasaccharide.
• Rapidly acting, within seconds of administration
• Fully synthetic, and thus should not trigger allergic reactions or immunogenicity
• Simply dosed, unlike the often complicated titration needed with protamine
• Simple to synthesize
• Robust activity in animal models of heparin antagonism with comparable activity to protamine
• Active in reversing the action of LMWH
• Demonstrate superior fibrokinetics (more normal clot formation) compared with protamine

By developing synthetic, universal anticoagulant antagonists, PolyMedix believes it is addressing a significant unmet medical need. Our Heptagonists are fast-acting antidotes to heparin and LMWH, and we believe should be able to be given whenever bleeding is diagnosed. Any extra Heptagonist dissipates rapidly, allowing resumption of anticoagulation as indicated. Procedure-related thromboprophylaxis can be reversed rapidly when intervention has ended, to avoid bleeding complications.

• The Status:
PMX-60056 has been selected as the lead IND clinical candidate. In vitro and in vivo data show that PMX-60056 and other compounds have potency comparable or superior to protamine, with potent activity against LMWH and Arixtra.

As the graphs below show, PMX-60056 completely reverses the action of heparin in an in vivo rat model, as quickly and as completely as Protamine.

In addition, experiments done in whole human blood of heparinized patients shows that PolyMedix's compounds completely reverse the action of heparin in these models. As is shown below, the action of PolyMedix's compounds is comparable to the reversal seen with Protamine.

PolyMedix has done numerous experiments using our heptagonists to reverse a variety of Low Molecular Weight Heparins. One of these experiments is shown below using the LMWH Tinzaparin and PMX-60056. PMX-60056 demonstrates superior in vitro neutralization activity versus protamine in the presence of human plasma.

The next steps being taken are to further evaluate and characterize PMX-60056 and other back-up compounds in a variety of animal efficacy and toxicology models. We plan to file an IND application for PMX-60056 by the end of 1Q 2008 to allow commencement of human clinical studies.

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