Intercept Cirrhosis Drug's Confirmatory Trial Could Face Design Changes

FDA advisory committee weighing obeticholic acid's accelerated approval for primary biliary cirrhosis will also consider whether enrollment criteria or design changes in ongoing clinical outcomes study are needed to support full approval down the road.

An FDA advisory committee's April 7 review of Intercept Pharmaceuticals Inc.'s obeticholic acid for accelerated approval to treat primary biliary cirrhosis could bring changes to an ongoing confirmatory trial.

FDA will ask the Gastrointestinal Drugs Advisory Committee whether any changes in the post-marketing trial's enrollment criteria or design would be necessary to support full approval of obeticholic acid (OCA) for the treatment of primary biliary cirrhosis (PBC), according to draft questions released April 5.

FDA's briefing document suggests some aspects of the confirmatory trial that the agency believes might need tweaking.

While the inclusion criteria allow for patients with a broader range of disease severity than were enrolled in the sole Phase III trial, it still is possible the same type of early-stage disease patients could end up enrolling in the confirmatory trial, the agency said. The confirmatory trial also is expected to generate little data on use of OCA as monotherapy.

The discussion point about Intercept's confirmatory trial is the panel's last question of the day, coming after six other discussion questions and a voting question on whether there is substantial evidence to support accelerated approval of OCA based on its effect on alkaline phosphatase (ALP).

One Approved Therapy

PBC is a rare, chronic, cholestatic liver disease that progresses to hepatic fibrosis, cirrhosis, hepatic decompensation and eventually death in the absence of liver transplantation.

Under a disease classification system based on biochemical parameters, early-stage disease is marked by normal total bilirubin, normal albumin and elevated ALP.

Moderately advanced disease is characterized by either elevated total bilirubin or low albumin, and elevated ALP. In advanced disease, ALP and total bilirubin are elevated while albumin is low.

Ursodeoxycholic acid (UDCA) is the only drug indicated for the treatment of PBC. It was approved in 1997 on the basis of three clinical trials, one of which included clinical endpoints such as death and transplant.

"While UDCA has a marked impact on clinical outcomes in PBC, up to 40% of UDCA-treated patients have a suboptimal or absent response to UDCA and, as such, are at significantly increased risk of an adverse outcome (death, requiring a liver transplant, or other clinical complications)," FDA's briefing document states.

Intercept is seeking approval of OCA, a farnesoid X receptor agonist, for the treatment of PBC in combination with UDCA in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate the older drug. The drug's user fee goal date has been extended by three months to May 29 (Also see "Intercept Using NDA Extension To Prep For AdComm Review And Launch" - Pink Sheet, 23 Feb, 2016.).

OCA also is in Phase III development for non-alcoholic steatohepatitis (NASH), a potentially significant market.

Accelerated Approval At Issue

The company is seeking accelerated approval in PBC on the basis of biochemical marker changes, including in ALP.

"FDA did not agree that ALP alone could be considered an acceptable endpoint to support marketing approval because of the lack of a clear link between changes in ALP (and other biomarkers as well) and long-term outcomes in patients with PBC," the agency's briefing document states. "FDA suggested that the applicant could use biochemical endpoints only if these biomarkers could be supported by a review of the literature and demonstrate that they are reasonably likely to predict clinical benefit."

Based on this advice, Intercept helped establish and collaborated with the Global PBC Study Group project to investigate the potential link between biochemical markers, particularly ALP and bilirubin, and clinical outcomes. The Global PBC Study Group is a multi-national registry study that followed nearly 5,000 adult PBC patients until they achieved a clinical outcome of death or liver transplant.

Findings from the Global PBC Study Group suggested that reduction in elevated levels of ALP and total bilirubin at 12 months predicted clinical benefit, in the form of transplant-free survival.

Based on this information, Intercept conducted a Phase III trial (747-301) that used a three-point primary composite endpoint: reduction in ALP below <1.67 times the upper limit of normal, total bilirubin ≤ULN, and ALP decrease of ≥15% from baseline at month 12.

FDA's review notes that the 216-patient Phase III trial enrolled primarily patients with elevated ALP levels but mostly normal bilirubin levels.

"Therefore, it is important to recognize that the results of clinical trial 747-301 apply only to a subgroup of PBC patients, i.e., patients with relatively milder disease, and that the subgroup of patients with both abnormal ALP and total bilirubin (patients with more severe biochemical manifestations) is too small to analyze and provide meaningful conclusions," the agency said.

"The primary endpoint evaluated in essence changes in only two of the three criteria, both related to changes in the same biomarker (alkaline phosphatase)."

In the pre-specified efficacy analysis conducted by FDA, both OCA treatment groups (10 mg and a titration arm that started at 5 mg and went up to 10 mg depending on patient tolerance and response) showed a statistically significant improvement in the proportion/percentage of patients achieving response at month 12 compared to placebo. There was a 46.6% response rate in the 10 mg group, 45.7% in the titration group and 9.6% in the placebo group (Also see "Intercept Liver Disease Strategy Bets Heavily On New Surrogate Endpoints" - Pink Sheet, 24 Mar, 2014.).

However, given differences in disease severity between the populations in the Phase III trial and the Global PBC Study Group, FDA reanalyzed the Phase III results against different ALP change cut points that the agency developed from a subset of patients in the global group that matched the characteristics of early-stage disease seen in the Phase III trial.

"Applying all of these explored ALP cut points at 12 months resulted in consistent relative differences in response rates between the treatment groups," FDA said.

FDA asks the committee to discuss whether evidence from the Global PBC Study Group supports use of ALP reduction as a surrogate endpoint reasonably like to predict clinical benefit in the treatment of early-stage PBC.

The agency also asks its advisors to discuss the adequacy of data supporting the use of OCA monotherapy in patients intolerant to UDCA.

The agency noted the Phase III trial included only 16 subjects (7%) treated with OCA monotherapy. This number "was too small to draw any conclusion regarding the effect of OCA use as monotherapy from this trial," FDA said.

However, combining these results with data from a Phase II monotherapy trial "did show a reduction in ALP in the OCA treated group relative to placebo," FDA said.

Trial Design Up For Debate

Intercept's confirmatory trial (747-302) began in December 2014 and is evaluating the effect of OCA on clinical outcomes such as all-cause death, liver transplant, end-stage liver disease score and hospitalization in PBC patients who have a mean ALP >5x ULN and/or mean total bilirubin >ULN and ≤3x ULN at baseline.

"During discussion with the applicant about the confirmatory trial design, the FDA noted that the ability of the applicant to retain patients in a placebo-controlled trial after OCA was marketed was a significant concern," FDA said. "Therefore, the applicant proposed that as a secondary study objective for supportive analysis purposes, [it would] utilize both historical control/observational groups from the UK-PBC and the Global PBC Study Groups. These historical control groups would, separately and in combination, be used as a comparator to the randomized OCA treatment group."

FDA said its review of the Phase III study identified a need for safety and efficacy data in patients with moderately advanced disease and advanced disease.

"The currently proposed enrollment criteria for the confirmatory trial is either TB >ULN and ≤3x ULN AND/OR ALP >5x ULN. While this is a broader range of ALP and TB elevations than was used for the Phase III trial, the AND/OR criteria for TB and ALP could allow the same early-stage patients to be enrolled in this confirmatory trial as were enrolled in the Phase III trial," FDA said.

In addition, the trial will not generate a significant amount of data on use of OCA as monotherapy because 95% of patients are expected to be on concomitant UDCA, the agency said.

FDA also notes that in the confirmatory trial all patients – even those who do not have a biochemical response to OCA – will stay on OCA for the length of the trial.

"The applicant has proposed that there is the potential for other pleiotropic effects based on in vitro data and nonclinical data from a different disease animal model," FDA said. "The potential utility of continuing treatment for patients who do not exhibit a biochemical response to OCA will not be answered with the current trial design."

Among the discussion questions for the panel, FDA asks the committee to consider the pros and cons of continuing OCA treatment in patients who do not demonstrate ALP reductions after six months of treatment. The agency also poses questions related to dosing regimens and use in moderate and advanced stages of disease.