• 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 uncommon, 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.

• Our Approach:

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 heptagonist IND clinical candidate, and phase I clinical trials began September 2008.

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.

• Clinical Studies:

Heparin Reversal

PolyMedix has successfully completed two Phase 1B/2 clinical studies with PMX-60056 to reverse heparin. Data from these studies is intended to support the development of a Phase 2 clinical trial in surgical patients.

In August 2010, we completed a Phase 1B/2 dose-ranging clinical study with PMX-60056. The clinical study was designed as an open label, dose titration study to evaluate PMX-60056 in the reversal of surgical levels of heparin, and also in allowing for the possibility of re-anticoagulation. Twelve healthy subjects were enrolled into two cohorts. Each of the subjects received either 200 U/kg or 350 U/kg of heparin, followed 20 minutes later by an initial ten-minute infusion of PMX-60056. Subjects then received additional infusions of PMX-60056 until the remaining heparin was fully reversed. Following the first reversal of heparin, a second dose of 100 U/kg of heparin was administered to achieve re-anticoagulation, which was then also reversed with PMX-60056. The data from this study shows that PMX-60056 met the study endpoints regarding both the reversal of varying heparin levels, and allowing re-anticoagulation and re-reversal.

PMX-60056 was generally well tolerated with no serious adverse events reported during the study. The most common side effect was a brief reduction in blood pressure that was seen only at the end of some reversals when ACT was already nearing baseline, and only after the last dose of PMX-60056.

In October 2009, we completed a Phase 1B/2 pilot efficacy study with PMX-60056. This study was designed as a double-blind, placebo-controlled, crossover study, with six healthy subjects. Each subject was given 70 U/kg dose of heparin followed twenty minutes later with either a single dose of 0.3 mg/kg of PMX-60056 or a placebo administered as a 10-minute intravenous infusion. With the crossover design, each subject received two dosing regimens, initially with heparin and either PMX-60056 or a placebo and then, two days after the first dose, with the alternative regimen (heparin and either PMX-60056 or placebo). Each subject thus acted as their own control.

PMX-60056 met the study safety and efficacy endpoints of this Phase 1B/2 study. In all subjects receiving PMX-60056, there was a rapid and complete reversal of the anticoagulant action of heparin, as measured by ACT and aPTT. Each subject’s minimum ACT and aPTT readings after being dosed with PMX-60056 were at or below the subject’s ACT and aPTT readings prior to being dosed with heparin. The heparin reversal appeared to occur at or before the end of the 10-minute infusion of PMX-60056, suggesting that the 0.3 mg/kg dose may have been in excess of requirements for 70U/kg heparin. Furthermore, the reversal was permanent: there was no return of anticoagulation during the hours required for heparin’s effects to decline naturally. In this study, there were transient changes in blood pressure that were not considered to be clinically significant and no serious adverse events were reported.

LMWH Reversal

PolyMedix has successfully completed a Phase 1B/2 clinical study with PMX-60056 to reverse low molecular weight heparin (LMWH).

In June 2010, we successfully completed a Phase 1B/2 clinical study to reverse low molecular weight heparin (LMWH) with PMX-60056. This study was designed as a double-blind, placebo-controlled, crossover study, with six healthy subjects. Each subject was given a subcutaneous injection of tinzaparin (Innohep®), an FDA approved LMWH to prevent the formation of blood clots, followed 5 and 8 hours later by two ten-minute intravenous infusions of PMX-60056 or placebo. With the crossover design, each subject received two dosing regimens, initially with tinzaparin and either PMX-60056 or a placebo and then, two days after the first dose, with the alternative regimen (tinzaparin and either PMX-60056 or placebo). Each subject thus acted as their own control.

PMX-60056 met the study safety and efficacy endpoints of this Phase 1B/2 study. In all subjects receiving PMX-60056, there was a rapid reduction in anti-Xa activity (a critical clotting factor) and a rapid and complete reversal of the anticoagulant action of tinzaparin, as measured by activated partial thromboplastic time (aPTT). Each subject’s minimum aPTT readings after being dosed with PMX-60056 were at or near the subject’s aPTT readings prior to being dosed with tinzaparin. The tinzaparin reversal appeared to occur at or before the end of the 10-minute infusion of PMX-60056, suggesting that the dose may have been in excess of requirements for reversal of the dose of tinzaparin. Furthermore, as tinzaparin continued to enter the subjects’ blood from the subcutaneous injection site, anticoagulation returned and a second ten-minute infusion of PMX-60056 was administered three hours later showing similar results. In this study, there were transient changes in blood pressure that were not considered to be clinically significant and no serious adverse events were reported.

[ Click here ] to view the PMX-60056 Bibliography

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