Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 μg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22–24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0–4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22–24 of PEDFIC 2 in sBAs was -201 μmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22–24 in sBAs were -144 and -104 μmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients

Do oscillations of insulin secretion occur in the absence of cytoplasmic Ca2+ oscillations in beta-cells?

That oscillations of the cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) in beta-cells induce oscillations of insulin secretion is not disputed, but whether metabolism-driven oscillations of secretion can occur in the absence of [Ca(2+)](i) oscillations is still debated. Because this possibility is based partly on the results of experiments using islets from aged, hyperglycemic, hyperinsulinemic ob/ob mice, we compared [Ca(2+)](i) and insulin secretion patterns of single islets from 4- and 10-month-old, normal NMRI mice to those of islets from 7- and 10-month-old ob/ob mice (Swedish colony) and their lean littermates. The responses were subjected to cluster analysis to identify significant peaks. Control experiments without islets and with a constant insulin concentration were run to detect false peaks. Both ob/ob and NMRI islets displayed large synchronous oscillations of [Ca(2+)](i) and insulin secretion in response to repetitive depolarizations with 30 mmol/l K(+) in the presence of 0.1 mmol/l diazoxide and 12 mmol/l glucose. Continuous depolarization with high K(+) steadily elevated [Ca(2+)](i) in all types of islets, with no significant oscillation, and caused a biphasic insulin response. In islets from young (4-month-old) NMRI mice and 7-month-old lean mice, the insulin profile did not show significant peaks when [Ca(2+)](i) was stable. In contrast, two or more peaks were detected over 20 min in the response of most ob/ob islets. Similar insulin peaks appeared in the insulin response of 10-month-old lean and NMRI mice. However, the size of the insulin peaks detected in the presence of stable [Ca(2+)](i) was small, so that no more than 10-13% of total insulin secretion occurred in a pulsatile manner. In conclusion, insulin secretion does not oscillate when [Ca(2+)](i) is stably elevated in beta-cells from young normal mice. Some oscillations are observed in aged mice and are seen more often in ob/ob islets. These fluctuations of the insulin secretion rate at stably elevated [Ca(2+)](i), however, are small compared with the large oscillations induced by [Ca(2+)](i) oscillations in beta-cells

Efficacy and Safety Outcomes With Odevixibat in Children With Progressive Familial Intrahepatic Cholestasis Due to Deficiencies in Multidrug Resistance Protein 3 (PFIC Type 3) or Myosin 5B (PFIC Type 6)

Hasan Özen1, Etienne Sokal2, Florence Lacaille3, Buket Dalgic4, Quanhong Ni5, Lise Kjems5, Patrick Horn5 1Hacettepe University Faculty of Medicine, Ankara, Turkey; 2Université Catholique de Louvain, Cliniques Universitaires Saint Luc, Division of Paediatric Gastroenterology and Hepatology, Brussels, Belgium; 3Paediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France; 4Department of Paediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey; 5Albireo Pharma, Inc., Boston, MA, USA Introduction/background: Progressive familial intrahepatic cholestasis (PFIC) is a group of rare, inherited liver diseases. Initial descriptions of PFIC were primarily based on data from patients with PFIC type 1 (PFIC1) or 2 (PFIC2). However, additional forms of PFIC have been identified. The ongoing, phase 3 PEDFIC 2 study is assessing the effects of odevixibat, an ileal bile acid transporter inhibitor, in patients with any type of PFIC. Aim: As of a data cut-off date of 4 December 2020, 6 patients with PFIC types other than PFIC1 or PFIC2 had enrolled in PEDFIC 2. Here, we describe efficacy and safety outcomes in this subset of patients, which comprises 5 patients with PFIC type 3 (PFIC3) and 1 with PFIC type 6 (PFIC6). Subjects and methods: In PEDFIC 2, all patients receive open-label odevixibat 120 μg/kg/day. Assessments include change from baseline in serum bile acids (sBAs), pruritus, hepatic biochemical parameters, growth, and sleep. Patient pruritus and sleep were evaluated twice daily by caregivers using the validated PRUCISION scale. Pruritus responses range from 0 to 4, with higher scores indicating worse symptoms. Other outcomes included proportion with sBA response (ie, sBAs reduced ≥70% or levels ≤70 μmol/L), proportion of positive pruritus assessments (PPAs) at the patient level (ie, pruritus score ≤1 or a ≥1-point drop from baseline), and treatment-emergent adverse events (TEAEs). Results: Patients with PFIC3 ranged in age from 3.7–13.3 years, and the 1 patient with PFIC6 was 12.8 years old at screening. All 6 patients were ongoing in the study at the data cut-off. Mean (range) exposure was 41 (34−54) weeks for the 5 PFIC3 patients and 54 weeks for the 1 PFIC6 patient. From baseline to last assessment, all patients had reductions in sBAs and all but 1 patient (PFIC3) had reductions in pruritus score. Mean changes from baseline to week 36 in sBAs, pruritus score, growth, sleep parameters, and liver parameters are shown in the Table. Three patients, including 2 with PFIC3 and 1 with PFIC6, met criteria for sBA response at last assessment. Over the interval from weeks 0–36, PPAs in 5 patients with available data were ≥85%. Overall, 5 of 6 patients experienced any TEAE; no patients had serious TEAEs or TEAEs leading to discontinuation. Summary and conclusion: Patients with PFIC3 or PFIC6 experienced clinical benefits with odevixibat, including reductions in sBAs and improvement in pruritus symptoms, growth, and sleep parameters. Odevixibat treatment was generally well tolerate