sPIF CLINICAL STUDY PROTOCOL IN AUTOIMMUNE HEPATITIS

The purpose of this study is to study the safety and tolerability of synthetic PreImplantation Factor (sPIF) in female patients with autoimmune hepatitis. Autoimmune hepatitis is a disease where the patient's immune system produces an inappropriate immune response against their own liver. PreImplantation Factor is a substance that is secreted by viable fetuses during pregnancy. PIF apparently initiates both maternal tolerance preventing the loss/rejection of the fetus. Synthetic PIF (sPIF) successfully translates PIF endogenous properties to pregnant and non-pregnant immune disorders. sPIF was found to be effective in preclinical models of autoimmunity and transplantation (published). Specifically sPIF protected the liver against immune attack. Toxicity studies (mice, dogs) have shown that high-dose sPIF administration for 2 weeks followed by 2 weeks observation period demonstrated a high safety profile. This study will evaluate the safety, tolerability and the blood level of this synthetic version of this natural compound in the circulation.

Both sPIF as well as natural PIF appears to orchestrate a complex series of cytokine effects that overall appear to cause return of proper immune function and regulation rather than a nonspecific immune suppression. PIF acts on both the innate and adaptive arms of the immune system in a dynamic, diverse and synergetic manner "per need". In the pregnancy setting, PIF maintains basal immunity required for embryo and maternal survival, and aids in tolerance for self by blocking activated T cells proliferation that would otherwise harm the embryo. The activity of PIF appears to have a dual complementary mode of action that is dependent on whether the immune system is in the basal or the stimulated immune state. The sPIF concentrations that were used are in the same range as those that are present in maternal circulation of viable pregnancy. sPIF targets three major intracellular proteins that pivotal in autoimmune control.

Eligibility Criteria:
Inclusion Criteria:

* Female, aged from 18 to 70 years old, of non-child bearing potential (to avoid the possibility if antibodies are formed to sPIF this could put the patient at risk for future fertility)
* Females must be either

  * Postmenopausal for greater than two years,
  * Postmenopausal for less than two years with an follicle stimulating hormone (FSH) level greater \> 40 million international units per milliliter (mIU/mL )
  * Or documented as surgically sterile (bilateral tubal ligation, bilateral oophorectomy or post-hysterectomy) at least three months prior to the screening evaluation
* Autoimmune hepatitis as documented by a:

  * Pretreatment score ≥15
  * Or a post-treatment score of ≥17 on the International Criteria for the Diagnosis of Autoimmune Hepatitis (Appendix 2)
* Treatment with prednisone and/or other oral, immunosuppressive drug(s) must have been stabilized for at least 6 weeks prior to screening for this study.
* Stable ALT levels with a fixed dose of their immunosuppressant medications
* Subjects do not have to have had a documented relapse after completion of an initial course of therapy
* Permitted concomitant immunosuppressant medications will include

  * Azathioprine dose equal to/or less 100 mg per day,
  * Budesonide dose equal to/or less 9 mg per day,
  * Mycophenolate mofetil equal to/or less 3000 mg per day,
  * Prednisone equal to/or less than 10 mg per day
  * Ursodeoxycholic acid equal to/or less than 1000 mg per day
* In the judgment of the Investigator, be in reasonable general health, based on review of the results of a screening evaluation (to include physical examination, measurement of vital signs, 12-lead ECG trace and the collection of blood and urine for routine clinical laboratory testing), performed no more than 30 days prior to Day 1 of study.
* Patients must agree to abstain from alcohol use during their participation in the study protocol.
* Alanine aminotransferase (ALT) levels of no more than five times the upper limit of normal (reference) range (ULN) at the screening evaluation.
* Normal renal function as determined by a serum creatinine
* A female of childbearing potential who is documented as either surgically sterile (bilateral tubal ligation, bilateral oophorectomy or post-hysterectomy at least 3 months prior to the screening evaluation) or post-menopausal for ≥ 2 years.

Exclusion Criteria:

* Any other forms of chronic liver disease.
* Decompensated liver disease defined on the basis of any one of the following laboratory parameters at the screening evaluation: total bilirubin \> 1.5 × ULN, prothrombin time \> 1.2 × ULN, platelets ≤ 100,000/mm3, or albumin \< 3 g/dL OR current or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy or variceal hemorrhage).
* Hemoglobin \< 11 g/dL at the screening evaluation.
* Serological evidence of infection with HIV upon review of the medical record.
* Evidence of hepatocellular carcinoma (i.e., screening α-fetoprotein \> 50 ng/mL or other standard of care measure).
* Subjects with, or a history of clinically significant oncologic, pulmonary, hepatic, gastrointestinal, renal, other cardiovascular, hematologic, metabolic, endocrine, neurologic, immunologic or hematologic illness or any other major medical disorder that, in the judgment of the Investigator, would interfere with subject treatment, assessment or compliance with the protocol or should otherwise preclude their participation in this trial.
* Have received therapy with potentially hepatotoxic drugs within 3 months (90 days) prior to Day 1 or are expected to receive such therapy during the study.
* Patient who are expected to receive a change in their immunosuppressant therapies during the protocol.
* Patients who may receive chemotherapeutic agents (e.g., corticosteroids, immunoglobulins and other immune- or cytokine-based therapies) during the study for any other medical condition.