New data fortify obeticholic acid role in NASH treatment

In the new analysis of the REGENERATE trial, the FXR* agonist obeticholic acid (OCA) was generally well tolerated and demonstrated a favourable safety profile in patients with nonalcoholic steatohepatitis (NASH).

“[The current data is] based on a robust safety assessment including >8,000 patient years and ~1,000 subjects exposed to the study drug for >4 years,” said NAFLD** expert Dr Mary Rinella from the University of Chicago Pritzker School of Medicine, Chicago, Illinois, US, during her presentation at DDW 2023. “[This represents] the largest safety database in the field of NASH.”

In the original phase III trial, participants were randomized 1:1:1 to receive placebo or OCA 10 mg (OCA10) or OCA 25 mg (OCA25) daily. The safety cohort (n=2,477 [2,187 F2/F3]) was a typical NASH population with respect to age (mean, ~55 years) and gender distribution (~60 percent female). About 85 percent met the criteria for metabolic syndrome. Over 60 percent of participants had mean LDL ≥100 mg/dL. [DDW 2023, abstract 451]

The incidence of treatment-emergent adverse events (TEAEs) leading to treatment discontinuation was higher in the OCA25 arm vs the OCA10 and placebo arms (22 percent vs 11 percent and 12 percent). This was largely driven by pruritus (11 percent). “The majority of pruritus AEs were mild to moderate in severity and were managed without any intervention,” noted Rinella.

Pruritus was also the most common AE of special interest with OCA in a dose-dependent manner. “Again, this has been demonstrated in the past and is not surprising due to the drug’s mechanism of action,” Rinella said.

CV events

There was a transient increase in mean LDL*** cholesterol, which peaked at 4 weeks but subsequently came down and reached near-baseline levels by month 18 in all patients. This effect was sustained through month 54. “In the first 12 weeks, there was an increase in LDL … and then reduction in VLDL. That is the general signal [observed. After which], presumably, an increase in LDL receptor expression happened,” Rinella explained.

“I think the LDL story is important [and] of big interest because of the risk of cardiovascular (CV) disease in this population, which is quite high … [CV events] are the most common cause of morbidity and mortality in this patient population,” she continued.

“[In the current study,] the absolute LDL increase over time is 9 mg/dL, so it really is not a huge change and it just equilibrates over time,” Rinella said.

Looking at adjudicated CV events, there was no difference across arms with respect to the percentage of subjects adjudicated with core^# (between 0.6 and 1.3 percent) or expanded MACE (4- or 5-point^##; between 1.0 and 1.8 percent).

Efficacy analysis using a consensus panel read

In the original analysis, there was an 11.2-percent difference in the fraction of responders between OCA25 and placebo (p=0.0002). Using the more rigorous consensus read method to assess the intention-to-treat cohort (n=931), a 12.8-percent difference was seen between the two arms (p<0.0001).

“Looking at patients with paired biopsies, those who received OCA25 were more likely to have improvement in fibrosis and less likely to have worsening in fibrosis. This was dose-dependent … More placebo patients worsened as well, suggesting that the effect is real,” said Rinella.

Reassuring data

“[Overall,] these are quite significant and very reassuring data,” Rinella said. “I think there is absolutely no doubt and we have seen repetitively that [the treatment effect] is consistent, so I think it is real and everything moves in the right direction.”

With respect to the LDL story, there appears to be no major signal at all, she added, and there was no evidence of excess CV risk.

“The confirmed antifibrotic effect, which has now been demonstrated several times with consistent magnitudes, along with long-term exposure data, supports a positive benefit:risk profile and chronic dosing of OCA in patients wth pre-cirrhotic fibrosis due to NASH,” Rinella concluded.

Managing pruritus might be the biggest difficulty, and given the lack of specific protocolized management of pruritus, this is up for discussion, she noted.