48-week data ASSERT odevixibat’s role in ALGS

Pooled analysis of the ASSERT and ASSERT-EXT studies show sustained improvements in multiple parameters with odevixibat in individuals with Alagille syndrome (ALGS), thus reinforcing its role in the treatment of this multisystem genetic disorder.

“In the published ASSERT study, odevixibat treatment resulted in statistically significant and clinically meaningful improvements in pruritus and reductions in serum bile acids vs placebo in patients with ALGS,” said Professor Ekkehard Sturm from the Children’s Hospital, University of Tuebingen, Germany.

“In [the current pooled] analysis, significant improvements in pruritus and sleep, and significant reductions in serum bile acids with odevixibat were sustained from baseline for up to 48 weeks in ALGS patients,” continued Sturm, who presented the findings at ESPGHAN 2024.

The rapid improvement in pruritus observed from weeks 1–4 were sustained up until weeks 45–48 (p<0.0001 vs baseline). A similar pattern of improvement was seen in serum bile acid levels across the evaluated timepoints (weeks 4, 12, 20–24, 36, and 48; p<0.0001 vs baseline). [ESPGHAN 2024, abstract 249]

Treatment with odevixibat also resulted in rapid improvements in several sleep parameters (days needing help falling asleep, days needing soothing, days sleeping with caregiver, tiredness) compared with baseline, with sustained effects for up to 48 weeks. Results across all timepoints yielded p values of <0.0001 vs baseline.

Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity and mostly abdominal complaints, Sturm said. Of note, one patient discontinued treatment owing to a nonserious grade 2 TEAE (increased blood bilirubin) on study day 115. “[However,] this patient already had increased bilirubin at baseline (75 µmol/L). When odevixibat was discontinued, the bilirubin level continued to rise, [reaching 140 µmol/L by day 141].”

Another patient with enteroviral gastroenteritis had grade 3 drug-related serious TEAEs (hematemesis and transient increase in international normalized ratio), but this resolved within 2 days without altering the odevixibat dosage, Sturm added.

IBAT inhibitor that may improve SoC in ALGS

“ALGS is associated with elevated bile acids in the liver and systemic circulation, which leads to severe pruritus and impaired sleep. Many of these patients need liver transplantation,” said Sturm.

Odevixibat is a potent selective ileal bile acid transporter (IBAT) inhibitor approved in Europe for the treatment of progressive familial intrahepatic cholestasis (PFIC) and in the US for the treatment of pruritus in individuals with PFIC and ALGS. [https://www.ema.europa.eu/en/medicines/human/EPAR/bylvay; https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215498s000lbl.pdf, accessed May 21, 2024]

The US approval of odevixibat for the treatment of ALGS was based on the ASSERT data, Sturm said. ASSERT met its primary and key secondary endpoints of improvement in pruritus and reduction in serum bile acids. [Lancet Gastroenterol Hepatol 2024;doi:10.1016/S2468-1253(24)00074-8]

Sturm and colleagues pooled data from ASSERT and ASSERT-EXT (n=52; mean age 6.5 years, 52 percent male) to further assess the effects of odevixibat on pruritus, serum bile acids, and sleep, as well as safety. In ASSERT, patients were randomized 2:1 to receive either odevixibat 120 µg/kg/day or placebo. In ASSERT-EXT, all patients were given odevixibat.

Median exposure to the drug was 73 weeks. A majority of participants (92 percent) had the JAG1 mutation, while the rest had NOTCH2 mutation. Ninety-eight percent of participants had used anti-pruritus drug at baseline. Mean scratching score using the PRUCISION observer-reported instrument was 2.6 (range of 0–4; higher scores denote worse symptoms).

“However, we have to keep in mind that the endpoints evaluated were not prespecified and no adjustments were made for multiple comparisons,” Sturm noted. “Hence, the biostatistical results from this pooled analysis should be interpreted with caution.”

“[Nonetheless,] overall, odevixibat effectively reduced systemic accumulation of bile acids and lessened the severity of pruritus for up to ~1 year. This indicates potential to improve the standard of care (SoC) in patients with ALGS,” Sturm concluded.