‘Rapid and durable response’ with seladelpar in patients with PBC and cirrhosis

The results, presented at the EASL Congress 2024 in Milan, Italy, showed “clinically meaningful improvements in markers of cholestasis with a durable effect up to 2 years and improved markers of liver injury,” reported Stuart Gordon, from Henry Ford Health in Detroit, Michigan, USA.

ASSURE, an ongoing phase 3 open-label study, includes patients from the RESPONSE trial and legacy parent studies investigating seladelpar, a potent and selective PPAR-delta agonist, in patients with PBC and an insufficient response or intolerance to first-line ursodeoxycholic acid.

The interim analysis presented looked at a subset of 35 patients with PBC and liver cirrhosis from the legacy parent studies only. These included a dose-ranging phase 2 study, a phase 3 long-term safety study, the phase 3 placebo-controlled ENHANCE study, and a 30-day phase 1b hepatic impairment study, with a gap between these and enrolment in ASSURE of around 700 days. Liver cirrhosis was based on the patients having one of the following:

• Evidence of cirrhosis on a historical liver biopsy;
• Current or prior history of decompensated liver disease;
• Liver stiffness according to more than 16.9 kPa on transient elastography;
• A combination of platelets below 140 x10³ per µL with a serum albumin level below 3.5 g/dL; an internal normalized ratio (INR) above 1.3, or a total bilirubin level above 1.0 times upper limit of normal (ULN);
• Radiologic evidence of cirrhosis; or
• Clinical determination by the investigator.
  
  

The participants were aged a mean of 60.8 years and the majority (91.4%) were women. Eight (22.9%) patients had portal hypertension and most (88.6%) were Child-Pugh class A. Liver stiffness by fibroscan at baseline was a mean 19.9 kPa and mean alkaline phosphatase (ALP) and total bilirubin levels were 245.4 U/L and 0.99 mg/dL, respectively. 

Gordon reported that based on analysis of all the data up to January 2024 most patients “achieved a rapid and durable composite biochemical response,” with daily seladelpar 10 mg, comprising an ALP level below 1.67 times ULN, a more than 15% decrease in ALP from baseline, and a total bilirubin level of no more than 1 x ULN.

At 6 months, 67% of 33 patients had achieved this response, which the presenter said was “in the most part maintained up to 24 months,” at which point the rate of response was 65% in 17 patients.

Similarly, the PBC patients with cirrhosis achieved rapid and durable ALP normalization, occurring in 29% of patients within a month and achieved by 49% of patients at 6 months, which was sustained at 12 months, and 24% at 24 months.

Gordon noted that the absolute reduction in ALP from baseline was a mean 38.1 percentage points at 12 months, whereas “total bilirubin remained stable” in this population of patients with cirrhosis. Both gamma-glutamyl transferase and aspartate aminotransferase levels decreased, with absolute mean reductions from baseline of 35.1 and 19.6 percentage points, respectively.

The presenter told delegates that “seladelpar appeared overall safe and well tolerated in this patient population.” There were 28 adverse events (AEs), with seven serious AEs. These serious AEs were “observed in individual patients without a particular pattern,” he pointed out. None of the events were thought to be related to treatment.

There were eight liver-related adverse events, three of which were of grade 3, including one case of anorectal varices and two serious adverse events – one case of increased bilirubin level and one case of hepatorenal syndrome that led to discontinuation of the drug.

Gordon concluded that “seladelpar has the potential to be an option for PBC patients with compensated cirrhosis.”

Similar findings were also reported at the conference for all 179 legacy patients with PBC participating in ASSURE alongside 104 from the 12-month RESPONSE primary analysis who received seladelpar 10 mg and 54 who crossed over to seladelpar 10 mg having received placebo.

These results, presented in a late-breaking poster, were “consistent with the pivotal phase 3 RESPONSE study,” wrote Palak Trivedi (University of Birmingham, UK) and colleagues, showing that seladelpar had “a [d]urable effect on markers of cholestasis and liver injury,” that were “maintained for up to 2 years.”

At month 12 of the ASSURE study, the composite biochemical response was achieved by 72.4% of 29 patients from RESPONSE who continued seladelpar treatment, 93.8% of 16 who crossed over from placebo, and 73.2% of 164 legacy patients. The corresponding rates of ALP normalization were 17.2%, 50.0%, and 42.1%.

The researchers also note that the reduction in pruritus seen with seladelpar in patients with a baseline numerical rating scale score of at least 4 points in the RESPONSE trial was “sustained” across the three cohorts in ASSURE.