FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis

The US Food and Drug Administration (FDA) has granted accelerated approval to Gilead’s seladelpar (Livdelzi) for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have had an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.¹

Announced on August 14, 2024, the decision is based on data from the phase 3 RESPONSE study, which showed 62% of patients treated with seladelpar achieved the primary endpoint of composite biochemical response at month 12 versus 20% of patients taking placebo.¹

According to a press release from Gilead, the approval makes seladelpar the first and only PBC treatment to achieve statistically significant improvements across key biomarkers, alkaline phosphatase (ALP) normalization, and pruritus versus placebo.¹ Of note, elafibranor (Iqirvo), which earned FDA accelerated approval for PBC in June, demonstrated biomarker improvement, ALP normalization, and a signal for pruritus benefit in the phase 3 ELATIVE trial, although the reduction of pruritus as measured on the PBC Worst Itch NRS score did not achieve statistical significance against placebo (LS mean, –1.93 vs –1.15; difference, –0.78; 95% CI, –1.99 to 0.42; P = .20). Itch was also assessed with 2 other secondary patient-reported outcome measures, and greater reductions in pruritus were observed with elafibranor compared with placebo at week 52, according to the itch domain of PBC-40 quality of life questionnaire (LS mean difference, -2.3; 95% CI, -4.0 to -0.7) and 5-D Itch total score (LS mean difference, -3.0; 95% CI, -5.5 to -0.5).²

According to the release, the seladelpar's accelerated approval is based on a reduction of ALP, and improvement in survival or prevention of liver decompensation events has not been demonstrated. Continued approval of seladelpar may be contingent on verification and description of clinical benefit in confirmatory trial(s). Additionally, seladelpar is not recommended for people who have or develop decompensated cirrhosis.¹

“More people are being diagnosed with PBC, impacting people of varied ages, gender, race and ethnicity. Those living with PBC share common symptoms, including incessant itching or skin-crawling sensations, as well as debilitating fatigue that is made worse by the itching at night,” said Carol Roberts, president of the PBCers Organization.¹ “The availability of a new treatment option that can help reduce this intense itching while also improving biomarkers of active liver disease is a milestone for our community.”

An oral, selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, seladelpar has been shown to regulate critical metabolic and liver disease pathways. It previously received FDA Breakthrough Therapy Designation for use in the treatment of PBC including pruritus in patients without cirrhosis or with compensated cirrhosis and PRIME status from the European Medicines Agency, as well as Orphan Drug Designation in the US and Europe for the treatment of patients with PBC.³

On February 12, 2024, the FDA accepted CymaBay Therapeutics’ New Drug Application for seladelpar and granted priority review with no plans to hold an advisory committee meeting to discuss the application. The NDA included data from across the seladelpar PBC clinical development program in more 500 participants with PBC, including from the placebo-controlled phase 3 RESPONSE and ENHANCE studies, the long-term open-label ASSURE study, and prior phase 2 studies.⁴

A phase 3, double-blind, placebo-controlled trial, RESPONSE evaluated the efficacy and safety of oral, once-daily seladelpar for 12 months in patients 18-75 years of age with PBC and an inadequate response to or a history of unacceptable side effects with UDCA. Participants were randomly assigned in a 2:1 ratio to receive oral seladelpar 10 mg daily or placebo, with the majority of patients receiving UDCA as standard-of-care background therapy. The primary endpoint was a biochemical response, defined as an alkaline phosphatase level < 1.67 times the ULN, with a decrease of ≥ 15% from baseline, and a normal total bilirubin level at month 12.⁵

Results showed a greater percentage of the patients in the seladelpar group elicited a biochemical response (61.7%) compared to those in the placebo group (20.0%; 95% CI, 27.7 to 53.4; P <.001), with findings generally consistent among patients with and without cirrhosis and among patients who received seladelpar alone versus those who received seladelpar with UDCA.⁵

Of note, normalization of the ALP level occurred in a greater percentage of patients who received seladelpar than those who received placebo (25.0% vs 0%; 95% CI, 18.3 to 33.2; P <.001). Among patients with moderate-to-severe pruritus at baseline, the reduction in the pruritus NRS score at month 6 was significantly greater in patients who were treated with seladelpar than in patients who received placebo (least-squares mean [LSM] change from baseline, −3.2 vs −1.7; LSM difference, −1.5; 95% CI, −2.5 to −0.5; P = .005).⁵

An open-label, long-term, phase 3 study, ASSURE evaluated the safety and efficacy profile of seladelpar 10 mg, once daily, for up to 155 weeks. The 2-year interim analysis, with a data cutoff date of January 31, 2024, included 179 participants from legacy studies and 158 participants from the phase 3 registrational RESPONSE study.⁶

Of the 99 participants from legacy studies who completed 24 months of treatment with seladelpar, 70% met the composite response endpoint, which includes ALP levels below 1.67 x ULN, a decrease in ALP levels of ≥ 15%, and total bilirubin levels at or below the ULN. In addition, 42% of these participants achieved ALP normalization at 24 months. Of the 164 participants from legacy studies completing 12 months of treatment with seladelpar, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.⁶

Among participants with baseline NRS ≥4, sustained improvement in pruritus was observed with a mean reduction of 3.8 and 3.1 points at 12 and 24 months in participants from legacy studies, respectively. For RESPONSE participants, a mean reduction of 3.8 was observed in both continuous and former placebo participants at 6 months in the ASSURE study.⁶

“People living with PBC have been waiting for treatment advancements for many years. Today’s approval of Livdelzi, with its distinct profile, provides them with an important new option,” Daniel O’Day, chairman and chief executive officer of Gilead Sciences, said in a press release.¹ “We look forward to leveraging Gilead’s long-standing expertise in liver disease to bring this promising new treatment to all those who could benefit.”

References

1. ^{Gilead. Gilead’s Livdelzi (Seladelpar) Granted Accelerated Approval for Primary Biliary Cholangitis by U.S. FDA. August 14, 2024. Accessed August 14, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/8/gileads-livdelzi-seladelpar-granted-accelerated-approval-for-primary-biliary-cholangitis-by-us-fda}
2. ^{Ipsen. The IQIRVO (elafibranor) Effect. https://www.iqirvohcp.com/efficacy}
3. ^{Gilead. Gilead Sciences Expands Liver Portfolio With Acquisition of CymaBay Therapeutics. February 12, 2024. Accessed August 9, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/2/gilead-sciences-expands-liver-portfolio-with-acquisition-of-cymabay-therapeutics}
4. ^{CymaBay Therpaeutics. CymaBay Announces FDA Acceptance of NDA and Priority Review for Seladelpar for the Treatment of Primary Biliary Cholangitis. February 12, 2024. Accessed August 9, 2024. https://www.prnewswire.com/news-releases/cymabay-announces-fda-acceptance-of-nda-and-priority-review-for-seladelpar-for-the-treatment-of-primary-biliary-cholangitis-302059522.html}
5. ^{Brooks, A. RESPONSE: Seladelpar Normalizes Alkaline Phosphatase, Reduces Pruritus in PBC. HCPLive. February 21, 2024. Accessed August 14, 2024. https://www.hcplive.com/view/response-seladelpar-normalizes-alkaline-phosphatase-reduces-pruritus-pbc}
6. ^{Gilead. Gilead’s Seladelpar Demonstrated a Sustained and Consistent Long-Term Efficacy and Safety Profile in Primary Biliary Cholangitis. June 5, 2024. Accessed August 9, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/6/gileads-seladelpar-demonstrated-a-sustained-and-consistent-long-term-efficacy-and-safety-profile-in-primary-biliary-cholangitis}