Odevixibat update for adult PFIC, older Alagille syndrome patients

PEDFIC2 trial

The first poster was presented by Henkjan Verkade (University of Groningen, the Netherlands) and colleagues who said their update suggests “that the efficacy and safety profile of [odevixibat] in adult patients with PFIC is comparable with the overall study population.”

The 72-week phase 3 clinical trial was open to patients of all ages with any type of PFIC. It included seven adults with elevated serum bile acids (sBA, ≥100 μmol/L), a history of significant pruritus, and an average itch score of at least 2 out of a possible 4 points on the patient-reported PRUCISION scale.

The team reports the outcome of these patients, all of whom were treated with daily odevixibat; six individuals at a dose of 120 μg/kg and one at a lower dose of 40 μg/kg. The median treatment duration was 20 months.

Among the patients, three men aged 22.5–25.3 years at enrollment had alterations to ATP8B1 leading to FIC1 deficiency (PFIC type 1), and two patients had alterations to ABCB11 leading to BSEP deficiency (PFIC type 2), namely a woman aged 19.5 years and a woman aged 26.0 years. The patients were diagnosed with PFIC between the ages of 13.5 and 17.5 years and received treatment with odevixibat for between 6 and 28 months.

“Most patients had elevated hepatic parameters at [baseline], which were variable over time with [odevixibat],” Verkade et al said, with all five patients achieving a “clinically meaningful” reduction in sBA from baseline and four also experienced a reduction in pruritus scores.

At last assessment, all patients had a reduction in alkaline phosphatase, four patients had reductions in alanine aminotransferase and aspartate aminotransferase, and three patients had lower levels of total bilirubin. One patient with PFIC type 1 had normalization of all hepatic biomarkers from high baseline measures.

Four of the five patients experienced treatment-emergent adverse events (TEAEs), including individual severe episodes of streptococcal septic arthritis, gastroenteritis-induced dehydration, and acute pancreatitis. However, there was only one TEAE considered possibly or probably related to odevixibat treatment, namely diarrhea and upper abdominal pain in a patient with PFIC type 2.

There were two patients with episodic cholestasis.

The first patient was male and 18.3 years of age at enrollment with an ABCB11 alteration. He was treated with a standard dose of odevixibat for a first emerging flare with clinically significant pruritus and elevated sBA or cholestasis, and continued treatment for 20 months before being transferred to the commercial agent. He experienced diarrhea for 11 days and ongoing abdominal pain considered possibly related to treatment, followed by a second 16-day episode of diarrhea requiring treatment interruption for 4 days.

The second patient, an 18.1-year-old woman with ABCB11 alterations and a history of annual episodic flares lasting 22–31 days with severe pruritus.  She was treated for the emerging flare with the lower dose of odevixibat for 14 months before being lost to follow-up. She experienced vitamin D deficiency, thought to be unrelated to treatment.

Verkade et al therefore concluded that odevixibat “can provide clinical benefit for adult patients with PFIC and warrants further investigation.”

ASSERT-EXT study

The authors of a second poster at the meeting also reported “clinically meaningful improvements” with odevixibat therapy for sBA and pruritus in children between the ages of 10 and 17 years with Alagille syndrome.

The phase 3 ASSERT-EXT study findings indicate that the safety profile of the IBAT inhibitor in this subgroup of older children “is favorable and comparable with the overall ASSERT study population,” which recruited participants from ages 6–12 months, reported Nadia Ovchinsky (Hassenfeld Children’s Hospital, NYU Langone, New York, USA) and co-authors.

The 10 patients in the current analysis were aged a median of 12.15 years and had been diagnosed with Alagille syndrome at a median age of 0.31 years. The majority were White (80%) boys (60%), and six of the patients completed the planned 96 weeks of treatment (median duration 74 weeks).

Two patients withdrew consent, one of whom transitioned to the commercial agent, one patient discontinued therapy following elevated bilirubin, and one patient discontinued treatment to undergo liver transplantation for ascites unrelated to odevixibat therapy.

Ovchinksy et al report that nine of the patients achieved a 1 point or greater reduction in their baseline scratching score, with pooled average pruritus scores decreasing from 2.1 points in the 10 patients at baseline to 0.4 points among the four respondents at weeks 69–72.

In addition, the average sBA level fell from 211.6 μmol/L at baseline to 76.8 μmol/L at week 72 for the six participants assessed at this timepoint.

“Patients had reduced sBA levels by 4 weeks that were generally sustained until last assessment,” the authors comment.

Indeed, eight patients had an sBA below 102 μmol/L at their last measurement, a threshold that “has been associated with improved native liver survival in patients with [Alagille syndrome],” they remark.

In addition, odevixibat treatment was associated with reductions in tiredness, and difficulties in both falling and staying asleep in all patients assessed at each of the timepoints up to and including the four assessed at weeks 93–96. Improved quality of life at last assessment was reported by caregivers for all 10 patients.

The investigators say that TEAEs were generally mild or moderate. The seven drug-related TEAEs included two cases of diarrhea and two cases of stomach pain that were thought possibly related to odevixibat therapy, all of which resolved without treatment disruption. Two patients had non-serious transaminase elevations that were possibly related to treatment, one requiring dose interruption, and one patient had grade 2 blood bilirubin elevation leading to discontinuation.

The team therefore concludes that odevixibat therapy “can provide clinical benefit for patients aged ≥10 to <18 years with [Alagille syndrome].”