Effects of TNX-832 (Sunol cH36) in Subjects With Acute Lung Injury/Acute Respiratory Distress Syndrome

The Safety, Pharmacokinetics, and Pharmacodynamic Effects of TNX-832 (Sunol cH36) in Subjects With Acute Lung Injury/Acute Respiratory Distress Syndrome

This Phase I/IIa, multi-center, randomized, placebo-controlled, single-blinded dose-escalation study evaluated TNX-832 (also referred to as ALT-836 and Sunol cH36) in subjects with suspected or proven bacteria-induced ALI/ARDS. Up to five cohorts of at least six subjects each were originally planned. Subjects were to be randomized in a 5:1 ratio to receive TNX-832 or placebo,respectively, administered as a single bolus infusion over 15 minutes. Three cohorts of subjects were enrolled to the study and safety and pharmacokinetics of the study treatment were evaluated.

Tissue factor (TF) is a transmembrane glycoprotein that acts as the principal initiator of the extrinsic coagulation pathway. TF is a key mediator between the immune system and coagulation and is the principal activator of coagulation. The TF-FVIIa complex activates FX and FIX, resulting in the cleavage of prothrombin to thrombin. Normally, localized activation of the coagulation cascade associated with inflammatory responses plays a role in controlling the spread of infectious agents; however, aberrant TF expression often leads to serious thrombotic disorders. TF-dependent thrombosis has been associated with many diseases including septic shock, coronary artery disease (CAD), cancer, and many inflammatory and autoimmune disorders such as lupus, rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are forms of acute respiratory failure characterized by diffuse pulmonary infiltrates, pulmonary hypertension, refractory hypoxemia, loss of pulmonary compliance and normal hydrostatic pressures. ALI and ARDS commonly occur in patients with acute catastrophic events such as sepsis, trauma and severe pulmonary infections. The incidence of ALI and ARDS is extremely high in patients with sepsis. By blocking the initiating events of extrinsic coagulation activation, their effects on pro-inflammatory events in the lungs and disordered fibrin deposition may be corrected and the evolution of severe structural and functional injury may be averted during ALI/ARDS. TNX-832 (formerly known as Sunol-cH36), directed against human TF, which can block the pathological complications of TF-dependent thrombus formation. The blockage by TNX-832 of initiating events in the extrinsic coagulation pathway may attenuate the effects on pro-inflammatory events in ALI/ARDS patients, thereby averting or decreasing disordered fibrin deposition and averting the evolution of severe structural and functional injury.

Inclusion Criteria:

1. ≥ 18 years

2. Suspected or proven bacterial infection

3. Receiving positive pressure ventilation through an endotracheal tube

4. Have ALI/ARDS, defined as having all of the following:

   • bilateral infiltrates consistent with pulmonary edema
   • Hypoxemia
   • no clinical evidence of left atrial hypertension

5. Provide signed informed consent

Exclusion Criteria:

1. Mechanically or chemically-induced ALI/ARDS (including burns, trauma, and near drowning)

2. End-stage lung disease

3. Decompensated congestive heart failure

4. Authorization to withdraw life support

5. Hemoglobin persistently <8.0 g/dL

6. Subjects who have any one of the following:

   • platelet count <50,000/mm^3
   • prolonged prothrombin time (PT)
   • prolonged activated partial thromboplastin time (aPTT)
   • having significant potential for disseminated intravascular coagulation (DIC)

7. Subjects who have two or more of the following:

   • prolonged aPTT
   • fibrinogen level below the lower limit of normal
   • presence of petechiae, ecchymoses, or other evidence of coagulopathy

8. Subjects who have a history of one or more of the following:

   • hematuria (microscopic or gross)
   • urinary tract neoplasia
   • nephrolithiasis
   • glomerulonephritis
   • active urinary tract infection (UTI)

9. Bleeding disorders within the past 6 weeks or vasculitis with diffused alveolar hemorrhage

10. Diagnosis of bleeding peptic ulcer disease within the previous 2 months

11. Congenital bleeding diatheses such as hemophilia

12. Treatment with anti-platelet, anti-coagulant agents, or non-steroidal anti-inflammatory drugs (NSAIDs)within 72 hours following infusion of study drug

    • Therapeutic heparin:

      • Unfractionated heparin within eight hours prior to study drug infusion
      • Low molecular weight heparins within the 12 hours prior to study drug infusion

    • Prophylactic heparin:

      • Unfractionated heparin >15,000 units/day
      • Low molecular weight heparins

    • Warfarin if used within 7 days prior to study drug infusion

    • Thrombolytic treatment within 3 days prior to study drug infusion

    • 8Glycoprotein IIb/IIIa antagonists within 7 days prior to study drug infusion

    • Aspirin or any aspirin containing compound within 3 days prior to study drug infusion

    • APC infusion within 72 hours prior to study drug infusion

13. Major trauma or trauma subjects at an increased risk of bleeding

14. History of severe head trauma that required hospitalization, intracranial surgery, or stroke or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion with an epidural catheter or who anticipate receiving an epidural catheter during study drug infusion

15. Major surgery within the previous 3 days, any postoperative subject with evidence of active bleeding, or any subject with planned or anticipated surgery within 72 hours after study drug infusion. History of abnormal bleeding during surgical procedures

16. Chronic renal failure, defined as a calculated glomerular filtration rate (GFR) ≤20 mL/min

17. Subjects with baseline aspartate transaminase (AST) or alanine transaminase (ALT) level >5 times the upper limit of normal. Subjects with known esophageal varices, chronic jaundice, biopsy proven cirrhosis, or chronic ascites

18. History of organ transplant (including bone marrow)

19. Subjects with malignancy having a life expectancy <6 months

20. Known human immunodeficiency virus (HIV) positive with CD4+ T Cell count <200/uL

21. Women who are pregnant or nursing

22. Participation in another clinical research study within 30 days before administration of study drug, with the exception of participation in studies involving noninvasive monitoring medical devices

23. Any prior treatment with a murine or chimeric antibody

24. Subjects who are moribund and where death is perceived to be imminent (within 72 hours after screening)

25. Subjects who have persistent hypotension not responding to fluid or vasopressor administration; subjects who require more than two vasopressors 26. Any medical condition which in the opinion of the investigator would interfere with optimal participation in the study or that would produce a significant risk to a subject