Pilot Study of Simtuzumab in the Treatment of Liver Fibrosis

Phase 2

Completed

Brief Summary: This study will evaluate the safety and tolerability of simtuzumab (GS-6624) in patients with fibrosis of the liver.

Up to 20 participants will be enrolled into two sequential cohorts. Cohort 1 will consist of 10 participants who will receive simtuzumab every other week for a total of 3 infusions. Participants in Cohort 2 (10 subjects) will also receive simtuzumab every other week for a total of 3 infusions; the dose will depend on the safety and tolerability of simtuzumab seen in Cohort 1.

Participants from both cohorts who have completed the main study will be allowed to continue on simtuzumab treatment for an additional extension period, and will receive up to 13 additional infusions of simtuzumab at a fixed dose of 700 mg for an additional 24 weeks.

Recruitment & Eligibility

Inclusion Criteria

Exclusion Criteria

Any evidence of hepatic decompensation past or present
Subjects currently abusing amphetamines, cocaine, opiates, or alcohol
Clinically significant cardiac disease
History of cancer, other than non-melanomatous skin cancer, within 5 years prior to Screening
Systemic fungal, bacterial, viral, or other infection that is not controlled
Use of systemic immunosuppressants within 28 days of the Pre-treatment Phase
Use of approved therapy for hepatitis C or hepatitis B virus within 28 days of the Pre-treatment Phase
Pregnant or lactating
History of bleeding diathesis within the last 6 months of study Day 1

Arm && Interventions

Group	Intervention	Description
Cohort 1	Simtuzumab	Participants will receive simtuzumab at a dose of 10 mg/kg by intravenous (IV) infusion every other week for a total of 3 infusions.
Cohort 2	Simtuzumab	Participants will receive simtuzumab IV every other week for a total of 3 infusions. The dose will depend on the safety and tolerability of simtuzumab seen in Cohort 1 but will not exceed 20 mg/kg.

Primary Outcome Measures

Name	Time	Method
Incidence of adverse events on multiple, escalating IV doses of simtuzumab	Through Week 14	The endpoints to be evaluated will include graded Adverse Events, laboratory abnormalities, and vital sign measurements

Secondary Outcome Measures

Name	Time	Method
Assessment of serum concentration of simtuzumab	Through Week 14	Trough concentrations will be summarized by day, treatment and dose.
Antibody formation to simtuzumab (anti-simtuzumab Abs)	Through Week 14	Immunogenicity endpoints will be geometric mean titer (GMT) and geometric mean fold rate (GMFR) for a select set of antibodies.
Measurement of pharmacodynamic (PD) markers after administration of simtuzumab	Through Week 14	Pharmacodynamic markers include: Tissue PD markers through mRNA expression, LOXL2, LOX, Other LOXL proteins, αSMA, Collagen 1A1, NFKB1, Caspase 1, SMAD, and NOD; Serum and plasma PD markers include: APRI, LOXL2, Osteopontin, Hyaluronic Acid, CXCL 9, 10 and 11, MMP1, MMP3, MMP9, TIMP1, CD40L, TGF-β1, ET-1, VEGF, GAL3, IL-6 / IL-8 / TNFα / IFNγ, α2-macroglobulin, Apolipoprotein A1.
Assessing the effects of chronic dosing of simtuzumab on liver structure and fibrotic markers	Up to 24 weeks	Measuring the effect of an additional 24 weeks of simtuzumab dosing on liver histology, LOXL2 and mRNA expression in the liver and serum markers of liver fibrosis