FX-06

 

a potential new drug for
prevention/ reduction of
vascular instability/ capillary leak in
Ebola Virus Disease

October 2014

Introduction

 

Ebola infections are characterized by immunosuppression and systemic inflammatory response that causes impairment of the vascular, coagulation and immune systems, finally leading to multi-organ dysfunction and death. Besides targeting the deadly virus, it is important to treat the devastating consequences of the virus infection namely edema formation, bleeding, severe hypotension and compromised respiratory, renal and cardiac function. Capillary instability, vascular leak and leukocyte migration are regarded as the underlying mechanisms leading to these very much feared complications in critically ill patients. FX06, a peptide representing a sequence of the human fibrin molecule, has been shown to counteract vascular leak and its fatal consequences – whatever was the leak causing agent (cytokines, thrombin, oxygen radicals, bacteria, virus). Efficacy has been proven in many different animal models of septic shock, hemorrhagic shock, reperfusion injury and acute lung injury. Especially noteworthy is the impressive effect on survival in dengue virus infected mice. These mice exhibit dengue shock syndrome which finally leads to vascular leak, organ failure and death. Treatment with FX06 reduces mortality up to 80 % and ameliorates vascular dysfunction. Treatment was started three days after infection when first disease signs could be observed. Clinical signs in EVD resemble those in dengue shock syndrome e.g. hemoconcentration, vascular leak and bleeding.
A human ph II study revealed efficacy in a disease associated with endothelial dysfunction/ vascular leak (prevention of reperfusion injury after myocardial infarction), a very high safety margin and extremely good tolerability.

 

Mode of action

The mode of action of FX06 is based on a fundamental mechanism of organ and tissue protection. The drugs amplify a natural protective mechanism in situations where its physiological concentrations are overwhelmed by patho-physiological events. The three-pronged therapeutic effect has been investigated in detail and includes prevention of vascular leak, prevention of leukocyte transmigration and reduction of vasoconstriction. Impressive biological activity was consistently demonstrated in different models

Efficacy in animal models of hemorrhagic and septic shock
FX06 has shown strong efficacy in rodent models of septic shock, including LPS induced shock and polybacterial sepsis, predicting therapeutic potential in this challenging indication. In acute and subchronic porcine models of trauma and hemorrhagic shock, organ protection of all major organ systems affected by shock and resuscitation has been observed using markers of tissue injury.
Efficacy in animal models of dengue virus induced shock syndrome
The clinical picture in dengue shock syndrome resembles the situation found in Ebola patients: hemoconcentration, hypotension, edema formation, vascular leak, bleeding and compromised respiratory and renal function. In several mice dengue shock models, FX06 has shown prevention of vascular leak in lung and intestine. Reduced vascular leak was associated with increased survival in mice.

 

Efficacy and safety in humans

Phase I

The safety, tolerability and PK profile in healthy human subjects has been established. A phase I study has confirmed the excellent safety profile of FX06. The drug has been given up to 1.35g per subject with only mild and non-systematic adverse effects. The pharmacokinetic data obtained in the study are comparable to the animal data.

Phase IIa (prevention of reperfusion injury after myocardial infarction)

Based on these results, a phase IIa trial in patients undergoing PCI for acute ST elevation infarction has been performed. The study tested the cardioprotective efficacy of 2×200 mg FX06 as bolus injection compared to placebo. 234 patients were randomized in this trial in 26 leading centers of interventional cardiology in 9 European countries.
Primary endpoint was the reduction of infarct size measured with cardiac magnetic resonance imaging. The most important finding from this trial was a statistically significant reduction of infarct necrotic core. Treatment with FX06 also leads to improved infarct healing and improved left ventricular function during the four month follow-up. Most encouragingly, this objective reduction of infarct size is accompanied by reductions of markers of myocardial necrosis, incidence and extent of microvascular obstruction and cardiac events.

Compassionate use in Ebola infected patients

Two emergency evacuated Ebola patients were treated in Germany (Frankfurt and Leipzig, respectively)in October 2014. Both had vascular leak as confirmed by different invasive and non- invasive methods. They received two different dose regimen:
1. Patient (38 years): 2 x 200 mg as bolus, 10 min. apart, every 12 hours for three consecutive days
2. Patient (56 years): 100 mg starting dose followed by infusion 200 mg/h
FX06 did not cause any obvious adverse reactions and a reduction in fluid accumulation in the lung could be observed indicating a decrease in vascular leak. The first patient is recovering, the second passed away due to massive overall bleeding.

Conclusion

FX06 exhibited excellent efficacy in many different animal models of vascular leak, including septic and hemorrhagic shock, dengue shock syndrome, acute respiratory distress, reperfusion injury and transplantation. In a human ph II study, the drug showed – besides efficacy – a very high safety margin and was tolerated extremely well. As the clinical signs in EVD resemble those observed in dengue shock syndrome, there is good reason to believe that the drug has a beneficial effect as supportive treatment in Ebola patients.
So far two patients with Ebola Virus Disease received FX06 under compassionate use. There a signs that a reduction of vascular leak occurs, however, as these patients are severely ill, efficacy has to be confirmed in more patients. Also pharmacokinetics and an optimal dose regimen has to be evaluated.
cGMP material of the drug is available in US and Europe which would facilitate a fast procedure.