Clinical Trials

ELAD® System Clinical Development

As of the end of Q3:2015, over 250 subjects have been treated with the ELAD System through prior trials and a compassionate use program. The largest trial was VTI-208, the Company’s Phase 3 randomized, controlled, open-label trial, evaluating the ELAD System in subjects with alcohol-induced liver decompensation (AILD).

In early 2013, we began enrollment in our Phase 3 clinical trial, VTI-208, in subjects with AILD and, in January 2015, completed enrollment of 203 subjects, the majority of whom were diagnosed with severe acute alcoholic hepatitis (sAAH). During 2014, we initiated enrollment in a second phase 3 trial, VTI-210, for subjects with sAAH and a phase 2 clinical trial, VTI-212, for subjects with acute liver failure (ALF), including fulminant hepatic failure (FHF) and surgery-induced acute liver failure (SILF).

In August 2015, we reported that our VTI-208 clinical trial failed to achieve both its primary and secondary endpoints. However, medically pertinent, pre-specified subsets based on age and lesser disease severity, as defined by lower Model for End-Stage Liver Disease or MELD scores, did show promising trends toward efficacy, in particular in those subjects without signs of acute kidney failure or severe coagulopathy. Subjects with acute kidney failure or severe coagulopathy appeared to have reduced tolerability for ELAD treatment. In this severely ill population, nearly all subjects reported adverse events, irrespective of treatment group, and these were of similar incidence, type and severity to those observed and reported in previous ELAD studies. Considering the results of the VTI-208 clinical trial and in an effort to focus our personnel and financial resources, we discontinued the VTI-210 and VTI-212 clinical trials.

VTL-308 Phase 3 Clinical Trial in Acute Alcoholic Hepatitis (AAH)

The VTI-208 analysis provided the rationale for our new Phase 3 clinical trial in AAH, referred to as VTL-308. The baseline criteria for VTL-308 include subjects with MELD 2.5, are excluded from this new study. Baseline serum total bilirubin (a measure of liver function) also must be ≥16 mg/dL in order to ensure a sufficient degree of liver disease severity. Applying these and key safety criteria to the analysis of the primary endpoint of overall survival in the ITT population, and assuming that this prospectively-defined population behaves similarly to this subgroup of the VTI-208 study along with other assumptions outlined in the statistical plan, a sample size for VTL-308 of 75 subjects in each the ELAD and control groups is consistent with a power of at least 95%.

We expect to enroll at least 150 subjects in VTL-308 at about 40 sites in the United States and Europe. Sites have been selected based on their high enrollment in the VTI-208 trial or their demonstrated capability to enroll these types of subjects. The first subject was enrolled in May of 2016, and we expect to report top-line results for VTL-308 around mid-2018.

VTI-208 Phase 3 Clinical Trial in Alcohol-Induced Liver Decompensation (AILD) which includes Severe Acute Alcoholic Hepatitis (sAAH)

On August 21, 2015, Vital Therapies announced that topline results from VTI-208 failed to meet the primary endpoint of overall survival through at least 91 days assessed using the Kaplan-Meier statistical method. Of 203 total subjects enrolled in VTI-208, 96 were randomized to the treated group and 107 were randomized to the control group. A hazard ratio of 1.027 (slightly favoring the control group) with a log rank p-value of 0.90 (not statistically significant, N.S.) indicated that there was no difference between ELAD-treated and control subjects in the primary endpoint.

Summary of Kaplan-Meier Analysis of Overall Survival
ITT Population, including VTI-208E through 12/31/15

ClinicalTrialGraph_01B

Note: Overall Survival includes data up to at least Study Day 91, with follow-up Protocol VTI-208E providing additional survival data up to a maximum of 5 years. Subjects with last contact day.  For all Kaplan Meier survival curves, the associated p-values are based on a comparison of survival curves using a log-rank test.

The secondary endpoints of proportion of survivors at study days 28 and 91 also showed no difference between the groups (Pearson’s Chi-squared p-values of 0.45 (N.S.) and 0.74 (N.S.), respectively).

In general, the incidence, type, severity, and outcomes of TEAEs and TESAEs in the VTI-208 study were similar to those seen in other studies of ELAD in similar patient populations (e.g. VTI-206 and VTI-201).

Treatment Emergent Serious Adverse Events (TESAE)

Safety Population ELAD Control Total
N = 95 N = 108 N = 203
n (%) n (%) n (%)

Number (%) of Subjects
Reporting Any TESAE
73 (76.8) 75 (69.4) 148 (72.9)

Number of TESAEs 156 168 324

VTL has conducted a series of pre-specified and post-hoc analyses of subsets of the VTI-208 data. Preliminary findings, which will need to be confirmed in a new clinical trial, include the following:

  • In a 120-subject, pre-specified exploratory subset of the intent-to-treat, or ITT, population with a MELD score of 28:
    • In the per protocol population for this subset (N = 116), the p-value was 0.059 (N.S.).
    • Furthermore, an analysis of 91-day survival in the ITT cohort revealed ELAD survival of 80.4% versus control survival of 65.2% (Pearson’s chi-squared p=0.068, (N.S.)).
  • In subjects with MELD scores of >28 at baseline, outcomes appeared to be worse in the ELAD group compared with the control group.
  • The ELAD and control groups appear to be balanced in this subgroup analysis with regard to baseline demographics and other key measures of liver disease.

Kaplan-Meier Subgroup Analysis of Overall Survival
including VTI-208E in ITT Subjects with MELD <28

ClinicalTrialGraph_02B

Of note, these results include 4 subjects who received liver transplants, including 1 in the ELAD arm at day 210, and 3 in the control arm at days 50, 90 and 329. A post hoc censoring of these subjects from the analysis at the time of transplant reveals a hazard ratio 0.575; p=0.075.

  • In another pre-specified exploratory analysis of a 101-subject sub-group with age less than the median age of 46.9 years, a Kaplan-Meier analysis of overall survival showed a hazard ratio of 0.634 with a log-rank p-value of 0.167 (N.S.) in favor of the ELAD-treated subjects.
    • Furthermore, an analysis of 91-day survival in this cohort revealed ELAD survival of 81.4% versus control survival of 67.2% (Pearson’s chi-squared p=0.112, N.S.).
  • In subjects with age greater than the median of 46.9 years, outcomes appeared to be worse in the ELAD group compared with the control group.
  • The ELAD and control groups appeared to be balanced in this subset analysis with regard to baseline demographics and measures of liver disease.

Kaplan-Meier Subgroup Analysis of Overall Survival
including VTI-208E in ITT Subjects <median age (46.9)

ClinicalTrialGraph_03B

Of note, these results include 2 subjects who received liver transplants, including 1 in the ELAD arm at day 210, and 1 in the control arm at day 329. A post hoc censoring of these subjects from the analysis at the time of transplant reveals a hazard ratio 0.638; p=0.171.

VTL-308 incorporates limits on age and factors associated with kidney dysfunction (creatinine) and blood clotting dysfunction (international normalized ratio, or INR), which are discrete components of the Model for End Stage-Liver Disease (MELD) score.

A post-hoc analysis of VTI-208, which serves as the basis for the design of the VTL-308 protocol, excludes subjects 50 years and older and also those with creatinine 1.3 mg/dL and above and INR above 2.5, in an attempt to avoid subjects with significant kidney and blood clotting dysfunction. In accord with this analysis, the 91-day survival rates were 93.9% for ELAD-treated subjects and 68.4% for control subjects. The full Kaplan-Meier curve is below:

Kaplan-Meier Subgroup Analysis of Overall Survival
including VTI-208E in ITT Subjects Age <50 years, Creatinine <1.3mg/dL, Bilirubin ≥16 and INR ≤2.5

ClinicalTrialGraph_04B

For more information on our previous clinical trials, please refer to our investor presentation on our investor relations page (http://ir.vitaltherapies.com/) or our SEC filings (http://ir.vitaltherapies.com/sec.cfm).