Clinical Experience with ELAD in Liver Failure

Clinical Experience with the ELAD System in Liver Failure

Prior to the initiation of our ongoing Phase III clinical trial program, over 145 subjects have received treatment with the ELAD System, including earlier iterations of the ELAD System, at multiple clinical sites in the United States, Europe, Asia and the Middle East in six randomized, controlled, clinical trials, one single-arm trial and a compassionate-use program. Currently, we have a Phase III randomized, controlled clinical trial fully enrolled and a second Phase III clinical trial underway. We also have enrolled our first subject in a Phase II clinical trial of the ELAD System in subjects with fulminant hepatic failure or surgery induced liver failure. Two early studies in acute liver failure were conducted using a different configuration of the ELAD System which involved circulation of whole blood to the VTL C3A cartridges rather than blood plasma. In these studies, 36 subjects were enrolled, of which 23 received treatment with the ELAD System and 13 were controls. The data from these studies led to the development of the next configuration of the ELAD System utilizing blood plasma and informed the design of the next clinical trials in acute liver failure.

The following table summarizes subsequent clinical trials as well as currently planned clinical trials using the later configuration of the ELAD System involving the treatment of blood plasma:

Trial Date Study Design Indication(s) Sites* Location(s) Total Subjects Enrolled
VTI-208
(Phase III)
Enrollment commenced March 2013 Randomized, controlled AILD 40+ U.S., Europe, Australia 203
VTI-210
(Phase III)
Enrollment commenced November 2014 Randomized, controlled sAAH 40+planned U.S., Europe 150+ planned
VTI-212
(Phase II)
Enrollment commenced June 2014 Single arm in Phase II component FHF and SILF 30+planned U.S. 40 planned
VTI-206
(Phase IIb)
2009-2011 Randomized, controlled AILD and other 26 U.S., Europe 62
Compassionate
-use program
2008-2010 Single-arm Various 6 U.S., U.K., Singapore, Saudi Arabia 16
VTI-201
(Phase IIa)
2008-2009 Randomized, controlled AILD and other 6 U.S. 18
VTIC-301
(Pivotal)
2006-2007 Randomized, controlled Various,primarily viral hepatitis 2 China 69
CR-202
(Phase II)
2002-2003 Randomized, controlled FHF 8 U.S., U.K. 19
PS-0698
(Phase I)
1999-2000 Randomized, controlled FHF 6 U.S., U.K. 25

*For ongoing trials, represents numbers of clinical sites which will fluctuate throughout the trials in part based on resources and competition between trials for patients.

Certain results from selected trials are described below:

VTI-206: Phase IIB Alcohol-Induced Liver Decompensation Trial

Between 2009 and 2011, we enrolled 62 subjects in a randomized, open-label, controlled Phase 2b clinical trial of treatment with the ELAD System in AILD and non-AILD subjects, which were two pre-defined and separately randomized cohorts. The clinical trial was conducted at 26 clinical sites in the United States and Europe. After discussions with the FDA, and to better inform our Phase 3 clinical trial, we adopted a 90-day overall survival endpoint. In each of the pre-defined cohorts, subjects were randomized in a 1:1 ratio to either treatment with the ELAD System plus standard therapy, or medical treatment in accordance with the standard therapy of the institution.

In January 2011, the trial’s Data Safety and Monitoring Board, or DSMB, reported that only the AILD cohort had the possibility of showing any treatment effect and therefore recommended that we discontinue the non-AILD cohort. This second cohort contained subjects with severe forms of chronic liver disease who would not be eligible for treatment with the ELAD System under our Phase 3 clinical trial criteria. Discussion with our FDA reviewer indicated the statistical analysis would be affected by closing the non-AILD arm, and therefore the study would not be able to serve as a pivotal trial. It was decided to terminate VTI-206 and design a new trial in AILD subjects. There were no unexpected ELAD System-related safety issues, as the DSMB did not detect any differences in the rates of serious events between the treated and control groups. Generally, the serious adverse events reported in this study were reflective of the severity of disease and co-morbidities present in the patient population. There were 67 serious adverse events reported by 35 subjects in this study, of which 6 events were reported as possibly or probably treatment-related, and consisted of gastrointestinal bleeding (1 subject), vomiting blood (1 subject), kidney failure (1 subject), reaction to blood infection (1 subject), vaginal bleeding (1 subject) and breakdown of red blood cells (1 subject). No serious adverse events were reported as definitely treatment-related.

The trial was terminated in April 2011 when 37 subjects had been enrolled in the pre-defined AILD cohort, which resulted in 29 subjects in the per protocol analysis due to elimination of eight subjects under pre-defined criteria. This subset showed a non-significant trend (p=0.27) toward improved 90-day survival of 69.2% in the ELAD System-treated group versus 43.8% in the control group. This trend is depicted in the figure below:

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Several clinical laboratory values, including bilirubin, creatinine, and sodium, were monitored for safety in this study. We believe that these parameters are also biomarkers pertinent to our understanding of the mechanism of action of the ELAD System in these subjects. As such, we conducted a post-hoc analysis evaluating the effect of the ELAD System and standard-of-care versus standard-of-care alone on these biomarkers. These data showed subjects treated with the ELAD System demonstrated positive trends which we believe are consistent with improvements in liver function. A fourth biomarker also included in liver failure algorithms, INR, is not presented because it is transiently and artificially impacted by the administration of anti-coagulant drugs used during treatment with the ELAD System.

The below charts depict trends of several biomarkers in VTI-206:

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Phase III Plan in AILD and AAH.

We used the input we received from both the FDA and EMA since January 2011 to design VTI-208, our Phase III program, which is primarily intended to support potential FDA approval in AILD, and VTI-210, which is primarily intended to support potential EMA approval in sAAH.

In March 2013, we enrolled the first subject in VTI-208, a 1:1 randomized, controlled, open-label pivotal trial designed to enroll 200 subjects with AILD. The VTI-208 clinical trial completed enrollment in January 2015 with 203 subjects having been enrolled at 40 clinical sites in the United States, United Kingdom and Australia. We expect to report topline results from VTI-208 clinical trial in the third quarter of 2015.  The study’s primary endpoint is overall survival up to at least study day 91 using a Kaplan-Meier survival analysis. VTI-208’s trial design is similar to that of VTI-206, although VTI-208 contains several elements designed to better focus the study on what we believe to be our addressable patient population. These changes include the addition of criteria intended to exclude subjects who are either too unstable to survive the first five days post-randomization, who have non-regenerable livers, or who have criteria suggesting that they are already recovering in the immediate pre-randomization period. Assuming a response pattern similar to the per-protocol subset analysis in VTI-206, the trial is 95% powered to reach a p-value of 0.05. A p-value of less than or equal to 0.05 means that there is at least a 95% probability that increased survival in the ELAD System treatment group is due to treatment with the ELAD System and not chance.

We have obtained regulatory allowance in the United States, United Kingdom, Germany, and Spain to begin enrolling subjects, have opened clinical sites for enrollment, and have commenced enrollment in VTI-210, a 1:1 randomized, controlled, open-label pivotal trial designed to allow for event driven clinical design (a statistical plan that allows the study sample size to be adjusted according to aggregate mortality) with a minimum of 150 subjects with sAAH who have failed seven days of treatment according to pre-defined criteria. The study’s primary endpoint is overall survival up to at least study day 91 using a Kaplan-Meier survival analysis.  Assuming a median survival of 45 days for the control group and 90 days for the ELAD System-treated group, the trial is 90% powered to reach a p-value of 0.05.  We currently project having database lock and topline results from the VTI-210 clinical trial in early 2017.

Pilot Trials in Fulminant Hepatic Failure (FHF)

Between May 1999 and August 2000, our predecessor company, VitaGen enrolled 25 human subjects with FHF in an open-label, randomized Phase I study, titled PS-0698, at six clinical sites in the United States and the United Kingdom comparing treatment with the ELAD System to medical treatment in accordance with the standard therapy of the institution. The ELAD System-treated subjects received either two or four cartridges, depending on body weight, with each cartridge containing 80 to 100 grams of VTL C3A cells. Of the 25 subjects enrolled, the first six subjects received treatment with the ELAD System, with the following 19 subjects randomized to, 10 treatment with the ELAD System (of which nine were treated) and nine controls. Between March 2002 and January 2003, VitaGen enrolled 19 human subjects with FHF in a Phase II open-label clinical study, titled CR-202, at eight clinical sites in the United States, with 13 subjects randomized to treatment with the ELAD System (of which 11 were treated) and six subjects randomized to standard-of-care. In CR-202, all the ELAD System-treated subjects received four ELAD cartridges containing 80 to 100 grams of VTL C3A cells.

Clinical study PS-0698 was designed to evaluate the safety of the ELAD System in FHF subjects. Clinical study CR-202 was designed to help inform future studies of the ELAD System in FHF. We believe the data from these preliminary studies are useful in evaluating the ELAD System’s potential as a treatment for FHF.

We believe the data from study PS-0698 suggest that the principal effect of treatment with the ELAD System is to allow severely ill patients with FHF to survive the first few days following study entry, so that they can receive a liver transplant. All of the control subjects who died did so within the first five days following their enrollment. All transplant subjects received their donor organs during this same time period. The ELAD System did not affect any other study variables associated with hepatic function or dysfunction. There were no serious adverse events reported that were considered by the trial investigator to be treatment-related.

In study CR-202, no intergroup differences in mortality were observed. Only two subjects, one treated and one control, died during the study. The proportion of subjects who received transplants was higher for treated subjects (54.5%) compared with control subjects (16.7%). Of the six subjects in the ELAD System group who received a transplant, three were not on the transplant list, unlike the single transplanted control who was listed. Generally, the serious adverse events reported in this study were reflective of the severity of disease and co-morbidities present in the patient population. There were 11 serious adverse events reported by seven subjects in this study. Three serious adverse events were determined by the trial investigator to be definitely treatment-related, which consisted of reduction in the number of blood platelets (1 subject), device malfunction (1 subject), and low blood pressure (1 subject). Five serious adverse events were determined by the trial investigator to be possibly or probably treatment-related, which consisted of reduction in the number of blood platelets (3 subjects), reduced body temperature (1 subject), and an increase in lactic acid (1 subject).

Neither study PS-0698 nor study CR-202 was designed to demonstrate a statistically significant improvement in overall survival or bridge-to-transplant/recovery (BTT/R). In neither case was a statistically significant improvement demonstrated. However, because inclusion criteria for these studies were similar and the endpoints were identical, we performed a post-hoc meta-analysis to explore the impact of transplant-listing on treatment outcome. While there was no evidence of an ELAD System treatment effect in the subset of subjects not listed for transplant, in the subset of subjects prospectively listed for transplant (N=26), this meta-analysis revealed positive survival trends. Moreover, as suggested by the study PS-0698 data alone, we observed additional benefit in the group treated with the ELAD System in BTT/R. While BTT/R is not an acceptable regulatory endpoint, we believe that it is clinically important, and these data have helped inform the design of our Phase III clinical trial in FHF.

In summary this meta-analysis revealed the following:

• thirty-day survival rates were 75% for the ELAD System-treated subjects and 50% for the control subjects (p=0.12);
• an analysis of Kaplan-Meier curves comparing success at a BTT/R endpoint revealed additional benefits for ELAD System-treated subjects (p=0.06); and
• a chi-squared analysis of the BTT/R status of subjects at the end of the study showed a statistically significant advantage for the ELAD System-treated subjects versus control subjects (p=0.03).

The overall survival trend of the meta-analysis is demonstrated in the following Kaplan-Meier chart on the left and the bridge-to-transplant or recovery of the meta-analysis is demonstrated in the following Kaplan-Meier chart on the right:

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Statistically significant differences were not observed for other outcome variables, including those related to hepatic function, in either the overall population or the subset.

Phase II / III Plan in Fulminant Hepatic Failure and Surgery Induced Liver Failure

We have enrolled our first subject in VTI-212, an open-label Phase II study that is part of a Phase II / III clinical program in subjects with either FHF or SILF. We are beginning this program with a Phase II single-arm component enrolling a planned 40 subjects, which may later be followed by a randomized, controlled Phase III component. Results from the initial Phase II single-arm component will be compared with historical or case-matched controls, and we currently anticipate Phase II data in 2016.

Since FDA guidelines provide for flexibility in review of marketing applications for life-threatening conditions, such as FHF and SILF, and because these conditions affect a small number of patients, it may be possible to seek marketing approval in FHF and SILF based on results from the Phase II single-arm component. However, regulatory agreement on an expedited approval pathway has not yet been sought and may never be granted. In the event that randomized or other Phase III data are necessary for approval in FHF and SILF, we expect to perform the randomized Phase III portion of the program or evaluate other Phase III trials, the design of which would be finalized upon analysis of the Phase II component. Data from VTI-212 may also be used to support our planned marketing applications for AILD and sAAH.

This trial is expected to be conducted primarily in the United States. The symptoms of FHF and SILF are similar, and we currently expect to use similar inclusion criteria for either population.

China Pivotal Trial in Acute Flare of Viral Hepatitis

Between 2006 and 2007, we enrolled 69 subjects with acute liver failure in a randomized, controlled open label trial at two hospitals in Beijing. Inclusion criteria focused the trial’s enrollment on subjects anticipated to have a 50% chance of death by 84 days, and the majority of enrolled subjects were experiencing an acute flare of viral hepatitis. The study was designed to enroll 120 subjects but was terminated early by one of the hospital’s ethics committee because, in light of the results discussed below, it would have been unethical to continue to treat control subjects with standard-of-care alone. Endpoints included survival at 14, 28, 56 and 84 days, as analyzed using a logrank method.

A significant protocol amendment was enacted after the enrollment of the first 49 subjects, in which inclusion criteria were changed, reducing the severity of disease, and a shorter ELAD System treatment time was recommended. This change in study design resulted in far fewer deaths or transplants in the second subset of 19 ELAD System treated and control subjects. A revised statistical plan was prepared to accommodate these differences in subject populations. Separate analyses were performed on the 49-subject subset and the full 68-subject population, and additional statistical analysis techniques were proposed, such as the use of Wilcoxon rank-sum techniques to analyze continuous variables such as survival time.

Analysis of the first 49 subjects (32 subjects randomized to be treated with the ELAD System for 3 days along with standard-of-care for the treating institution and 17 subjects randomized to be treated with standard-of-care alone) revealed the following:

• significant differences in 28- and 56-day survival using the logrank test (p=0.015 and 0.026 respectively);
• significant differences in 84-day survival using the Wilcoxon test (p=0.049) (logrank was not significant at 14 and 84 days, p=0.074 and 0.058, respectively); and
• no unexpected safety issues.

Generally, the serious adverse events reported in this study were reflective of the severity of disease and co-morbidities present in the patient population. There were 16 post-treatment adverse events in 8 of the 32 treated subjects that the investigators reported as possibly or probably treatment related.

These efficacy results are depicted in the below Kaplan-Meier curve:

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Analysis of all 68 subjects treated (44 subjects randomized to be treated with the ELAD System for 1 to 3 days along with standard-of-care for the treating institution and 24 subjects randomized to be treated with standard of care alone) revealed the following:

• Significant differences in 28-day survival using the logrank test (p=0.015);
• No significant differences in 14, 56, and 84-day survival using the logrank test; and
• No unexpected safety issues.

Based on these results, it was concluded that the Wilcoxon test is a more sensitive technique to elucidate differences between groups in the ELAD System clinical trials, and that a more severely diseased population and more extended treatment times should be evaluated in future clinical studies. Future clinical trials may be analyzed using the more conservative logrank technique.

One further observation from the 49 subjects in the first part of this study was that the ELAD System can significantly decrease bilirubin levels, an important biomarker of liver function in patients with acute liver failure. The overall magnitude of the decrease in mean end of treatment total bilirubin in the ELAD group was 25.1% (17.5 to 13.1 mg/dL) compared to an increase in the control group of 36.8% (17.1 to 23.4 mg/dL). Serum sodium, another biomarker associated with survival in subjects with acute liver failure, also was significantly improved in the subjects treated with the ELAD System relative to control subjects.

These China pivotal trial data formed the basis of a submission for marketing approval to the China FDA, or CFDA, in September 2007. It should be noted that this study was not designed, and will not be used, as a pivotal trial to support approval of the ELAD System in the United States and Europe.

Subsequent to the completion of the VTIC-301 clinical study, an additional protocol was prepared by the treating physicians to explore the long-term survival of subjects enrolled in this study. Following the grant of informed consent, subjects enrolled in VTIC-301 were contacted and invited to return to the treating hospital for examination for recurrence of liver disease or the incidence of cancer. This study was carried out in 23 and 22 subjects, respectively, 3 and 5 years following initial randomization.

These data from the first 49 subjects suggest that the survival benefit (statistically significant at 3 years and 5 years, p<0.05, logrank) afforded to those subjects treated with the ELAD System is maintained over a 3 and 5 year period relative to those subjects in the control group. These trends are depicted in the Kaplan-Meier curves below:

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While these follow-up analyses were not prospectively defined in the VTIC-301 protocol, we believe they provide valuable information on the long-term survival of this group of patients.

The results of VTIC-301 were submitted to the CFDA for marketing approval in September 2007. However, a regulation enacted in 2009 prevents the approval of novel foreign medical products until they are approved in their home markets first. Our application in China is pending.

Future Clinical Development Plans

In the future, we anticipate pursuing clinical development of the ELAD System in additional indications, including bridge-to-transplant.