Odevixibat reduces bile acids, improves sleep, pruritus in Alagille syndrome

Patients with Alagille syndrome (AS) may benefit from treatment with odevixibat, with the phase III ASSERT study showing that its use results in rapid, sustained, and highly significant improvements in pruritus, sleep quality, as well as decreases in bile acids (BAs). Odevixibat is also well tolerated.

“AS is a rare, multisystem disorder caused by mutations in JAG1 or NOTCH2 with hepatic manifestations that include elevated BAs and pruritus associated with impaired sleep and quality of life,” said the researchers, led by Nadia Ovchinsky, paediatric gastroenterology, hepatology, and nutrition, Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, US.

The findings of ASSERT were recently presented at the ESPGHAN 2023.

In this study, Ovchinsky and her colleagues randomized patients with a confirmed AS diagnosis, history of significant pruritus, and elevated BAs in a 2:1 ratio to receive either odevixibat 120 μg/kg/day or placebo. They assessed the change in observer-reported scratching score from baseline to 6 months (primary endpoint). Other endpoints evaluated were the change in serum BAs from baseline to weeks 20 and 24, and change in sleep parameters from baseline to month 6.

The researchers also assessed safety by monitoring for treatment-emergent adverse events (TEAEs) and reported two-sided p-values.

Fifty-two paediatric patients (mean age 6.3 years) were treated with either odevixibat (n=35) or placebo (n=17), all of whom completed the study. Use of odevixibat for 24 weeks was significantly associated with clinically meaningful improvements in pruritus at month 6 compared with placebo (p=0.0024). In addition, these changes occurred rapidly and were sustained. [ESPGHAN 2023, abstract H-O022]

Significant reductions in BAs also occurred at the average of weeks 20 and 24 with odevixibat relative to placebo (p=0.0012). Patients who received odevixibat also showed improvements in several sleep parameters at month 6 compared with placebo.

No significant between-group differences were seen in the incidence of TEAEs (23 percent vs 18 percent). Specifically, the incidence of treatment-emergent and drug-related diarrhoea was 29 percent and 11 percent with odevixibat, respectively, and 6 percent each with placebo.

Extension study

These findings were confirmed by the interim results from the open-label, phase III ASSERT-EXT study, which was also presented at ESPGHAN 2023.

Analysis of the ASSERT-EXT data revealed that odevixibat led to rapid improvements in pruritus, sleep, and BAs among treatment-naïve patients with AS. Likewise, those previously treated with odevixibat had sustained improvements in these outcomes with continued treatment. Use of the study drug for at least 24 weeks was also well tolerated. [ESPGHAN 2023, abstract H-O023]

Mild-to-moderate TEAEs were reported by most patients with AS, but two out of 49 (4 percent) experienced serious TEAEs. The incidence of treatment-emergent and drug-related diarrhoea was 16 percent and 4 percent, respectively. Drug-related serious TEAEs or those that led to treatment cessation or dose reduction were not reported.

Patients who completed ASSERT were enrolled in the ASSERT-EXT study and were administered odevixibat 120 μg/kg/day. Two cohorts were assessed until the interim cutoff on 9 September 2022, namely treatment-naïve patients (ASSERT participants who received placebo) and those who received odevixibat in ASSERT). The researchers then evaluated the following outcomes: pruritus, serum BAs, sleep, and TEAEs.