Perspective from Keith D. Lindor, MD, FAASLD
April 07, 2016
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Advisory Committee unanimously recommends approval of OCA for PBC

Perspective from Keith D. Lindor, MD, FAASLD
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The Gastrointestinal Drugs Advisory Committee voted 17-0 in favor of Intercept Pharmaceuticals’ new drug application of obeticholic acid for use as monotherapy or in combination with ursodeoxycholic acid for the treatment of adults with primary biliary cirrhosis, also known as primary biliary cholangitis.

Committee members cited an unmet need in this community as a reason for accelerated approval.

“There is an unmet need and I do think there are more studies needed to be carried out, but no concerns with the current dose proposed,” Marina Silveira, MD, physician, Louis Stokes Cleveland VA Medical Center, said after voting at the meeting.

Kris Kowdley, MD, FACP, FAASLD, director of the Liver Center Network and Research, Swedish Medical Center, Seattle, spoke about the history of primary biliary cirrhosis (PBC) and the lack of treatment since ursodeoxycholic acid, the only treatment option for PBC, was approved by the FDA.

Kris V. Kowdley, MD, FACP, FACG, AGAF, FAASLD

Kris Kowdley

“Since 1997, ursodeoxycholic acid has been the cornerstone of therapy, but treatment has been suboptimal or intolerable, pressing the need for other therapies to be available,” Kowdley said during his presentation.

During the manufacturer presentations, researchers and Intercept representatives presented data on obeticholic acid (OCA; Intercept Pharmaceuticals) from the phase 2 and 3 clinical studies in which improved plasma alkaline phosphatase (ALP) was evident in patients with PBC after treatment with OCA.

Safety and Efficacy 

Leigh MacConell, PhD, vice president of clinical development at Intercept Pharmaceuticals, spoke to the efficacy of OCA, evaluated in approximately 430 patients with PBC, including a subset of patients exposed to PBC for 5 years. Patients were enrolled in two phase 2 clinical trials and one phase 3 trial.

“First, the phase 2 study evaluated OCA as combination therapy in patients with failed response to UDCA. The primary endpoint was met and all doses of OCA supported 25% improvement in ALP after 3 months,” MacConell said during her presentation. “The second phase 2 trial evaluated OCA as monotherapy. … The study met the primary endpoint and there was a significant improvement up to 40% after 3 months. In the phase 3 trial, the primary endpoint was achieved and the treatment provided benefit in terms of biochemical treatment that was not achieved with standard care alone.”

Roya Hooshmand-Rad, MD, PhD, executive director of medical safety and pharmacovigilance at Intercept Pharmaceuticals, stated during her presentation that the majority of the safety data are from patients exposed to PBC for 1 year and treated for at least 2 years.

“Overall, our data collectively indicate that OCA was safe and well-tolerated with best tolerability observed in patients who began treatment at 5 mg. Pruritus is common with PBC and was reported as an adverse event, but it was manageable, especially in the titration arm where only one person discontinued treatment due to it,” Hooshmand-Rad said.

After reviewing the safety data, Ruby Mehta, MD, medical reviewer for the FDA, stated in her presentation that OCA doses higher than 10 mg may not provide any further benefit in terms of reducing ALP and more data are needed.

“Additional safety data are needed in patients with moderately advanced stage disease for use in monotherapy in patients intolerant to UDCA and patients who develop HDL reductions,” Mehta said.

MacConell said a phase 4 clinical trial is ongoing that includes 350 patients with PBC across 150 clinical sites in 28 countries.

Lara Dimick-Santos, MD, cross discipline team leader at the FDA, discussed briefly the design of Intercept’s phase 4 clinical trial and stated the FDA has several issues with the design.

“We would like to see clinical benefit is confirmed across the entire spectrum of PBC disease and additional data on the use of OCA as monotherapy,” Dimick-Santos said. 

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Statistical analysis

After conducting an analysis based on global PBC clinical data, the FDA proposed a stratified cutoff for ALP patient inclusion criteria, different from Intercept’s, that demonstrated a wider separation, according to data presented by Min Min, PhD, statistician in the office of biostatistics at the FDA.

“The FDA’s proposed stratified cutoff, less than two times the upper limit of normal and a 40% decrease in ALP or less than 1.67 times the upper limit of normal and at least 15% decrease, has demonstrated numerically better performance than the applicant’s cutoff. Subgroup analysis results demonstrate that the estimated hazard ratios of association between the cutoffs and the clinical outcomes appears to be consistent,” Min said.

In committee discussion, a member stated that in terms of a cutoff, “simpler is best.”

Dosage recommendations

Intercept’s application requested approval for a 5 mg dose of OCA with titration to 10 mg for patients with PBC.

“The proposed starting dose of 5 mg [of OCA] with up-titration to 10 mg after 3 months is appropriate for the overall population [of patients with PBC],” Dhananjay Marathe, PhD, senior pharmacometrics reviewer for the FDA, said during his presentation. “In the phase 3 trial, there was better tolerability with time with a lower starting dose.”

Marathe continued to say that titration from 5 mg to 10 mg led to further ALP reduction. However, the FDA proposes that for moderate and severe hepatic impaired patients, they start treatment at 5 mg once weekly, titrate to 5 mg twice weekly, then 10 mg twice weekly after 3 months.

“The only difference in the applicant’s recent proposal is they wanted 5 mg dose every other day. This is not recommended due to high plasma exposures,” Marathe said.  

Public comment, committee discussion 

Both patients and organizations urged the committee toward approval during public comment.

Carol Roberts, patient with PBC and member of the PBCers, an online support group for patients, presented a letter with 1,500 signatures from families and patients affected by PBC.

“Simply put, PBC patients need another option,” Roberts said during public comment. “It’s time for new drugs to come to help more PBC patients live longer with the liver they were born with. We need this approved and we need it now.”

A statement was read on behalf of Thomas F. Nealon III, chairman of the board of directors and CEO of the American Liver Foundation, that stated: “We believe all people with liver disease deserve options. We believe that all efforts should be made to delay transplantation. … We strongly support efforts by Intercept and other companies who [try to make this a possibility]. We respectfully ask the committee to accelerate this approval.”

During committee discussion, there was a question as to if there are sufficient data for patients with advanced PBC. Multiple committee members stated this has been “controversial” and one said there are not enough sufficient data to conclude the use of OCA for this subgroup of patients.

Lin Chang, MD

Lin Chang

“I voted yes considering all data and weighing the risks and benefits of the medication, especially in patients with PBC who have limited treatment options,” Linda Feagins, MD, associate professor of medicine, division of digestive and liver diseases, University of Texas Southwestern Medical Center, said after the vote. “I think it’s very reasonable to go forward and I’m more comfortable [knowing] phase 4 data will be coming out.”

Lin Chang, MD, professor of medicine and program director of the University of California, Los Angeles, GI Fellowship Program, said she voted yes because of how it will benefit patients who don’t have any treatment option.

“It fulfills an unmet need and I can hear what the patients were saying today and I appreciate that.” – by Melinda Stevens

Disclosure: Kowdley reports a financial relationship with Intercept. MacConell and Hooshmand-Rad are employed by Intercept. All others quoted report no relevant financial disclosures.