The findings “support progression to phase 3 development of the sustained release formulation of BZF with low doses of OCA,” say Cynthia Levy (University of Miami, Florida, USA) and colleagues in a poster presented at The Liver Meeting 2023, held in Boston, Massachusetts, USA.

The two randomized studies – 213 and 214 – compared a range of doses and formulations of OCA plus BZF combined with BZF monotherapy for 12 weeks in patients with PCB who had an inadequate response or were intolerant to ursodeoxycholic acid (UDCA).

In both studies, the participants had alkaline phosphatase levels that were at least 1.5 times the upper limit of normal (ULN) and total bilirubin levels that were up to twice the ULN.

In study 213, patients were assigned to receive OCA 5 mg titrated to 10 mg at week 4 alongside once daily BZF 200 mg immediate release (B200 IR) or BZF 400 mg sustained release (B400 SR), or B200 IR or B400 SR as monotherapy for 12 weeks.  

The treatment arms in study 214 were OCA 5 mg with no titration plus BZF 100 mg/day immediate release (B100 IR) or BZF 400 mg/day immediate release (B400 IR), or B100 IR or B400 IR alone.

The median daily dose of UDCA at baseline was 14.1 mg/kg in study 213 and 11.4 mg/kg in study 214. The mean age of the participants was 55.4 years and 53.7 years, respectively, and most of the participants in both studies were White (89.3% and 95.1%) and women (93.3% and 92.7%).

The patients were considered to have biochemical remission at 12 weeks if they had alkaline phosphatase (ALP), gamma-glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase levels that were on or below the ULN and a total bilirubin level of no more than 0.6 times above the ULN.

Top line results for the 75 patients in study 213 and a planned interim analysis of the first 41 of 72 patients in study 214 showed that patients taking OCA plus B400 SR or IR (n=18 and 10, respectively) were the most likely to achieve this outcome, at a rate of 44.4% and 40.0% of patients, respectively.

This compared with corresponding rates of 31.6% and 18.2% with B400 SR or IR monotherapy, respectively, although differences between combination OCA/BZF and BZF were not significant across the various groups.

At baseline, the median ALP was 238 U/L in study 213 and 263 U/L in study 214, and a significant reduction was seen with OCA plus B400, irrespective of BZF formulation and OCA titration, versus B400 monotherapy in both studies. In study 213, ALP levels at week 12 were reduced by 60.6% versus 46.4% and in study 214 by 65.4% versus 53.2%.

Total bilirubin levels, which were a median of 8.0 and 8.7 µmol/L in studies 213 and 214, respectively, at baseline were also reduced by a corresponding 24.7% and 21.1% with OCA plus B400 by week 12, but there was no significant difference compared with B400 monotherapy.

The results showed that treatment-related adverse events (TRAEs) were generally comparable across treatments in both studies. There were two severe TEAEs in study 213 – hypertension with B200 IR and pruritus with OCA plus B400 SR – the latter of which led to discontinuation. In study 214, there was one case of severe pruritus with OCA plus B100 IR, but there were no discontinuations.

New and worsening pruritus occurred in 11% of 18 patients in study 213 taking OCA plus B400 SR, which is “substantially lower” than the 56% rate seen with OCA 5–10 mg in the phase 3 POISE study, note Levy et al.

However, the rate was higher, at 70%, among the 10 patients in study 214 taking OCA plus B400 IR, which the researchers believe could be due to the difference in the B400 formulation.

They conclude that their data “suggest that the short-term administration of OCA/BZF was generally well tolerated and has therapeutic potential to normalize multiple serum biomarkers.”