Objective To assess whether the degree of steatosis as determined by controlled attenuation parameter (CAP) measurements correlates with that observed on liver biopsies in a single-center pediatric ...and young adult cohort. Study design This cross-sectional study included patients undergoing liver biopsy as part of standard clinical care between January 25, 2012, and April 1, 2015, at Boston Children's Hospital. Eligible patients, with a variety of liver diseases, had CAP measurements within 1 year of biopsy. CAP values were compared across histologic steatosis grades using ANOVA. Results Sixty-nine patients (mean age, 16.0 ± 2.9 years; 62% male) were studied. CAP measurements were obtained at a median of 1.3 months (IQR, 0.5-3.2) after biopsy. Of the 69 subjects, 23 had steatosis on biopsy. Mean CAP value (dB/m) for subjects with no steatosis was 198 ± 37 vs 290 ± 47 for subjects with steatosis ( P < .0001). There were statistically significant differences between CAP values in individuals with no steatosis vs mild/moderate steatosis ( P < .0001), no steatosis vs marked steatosis ( P < .0001), and mild/moderate vs marked steatosis ( P = .004). Conclusion This study demonstrated a difference in CAP between no steatosis and steatosis, and between grades of steatosis. CAP may be a useful noninvasive tool to detect hepatic steatosis in children.
Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid ...transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome.
ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1–18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0–4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment.
Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years SD 4·25) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference –117 μmol/L, 95% CI –232 to –2). From baseline to week 48, sBA (–96 μmol/L, –162 to –31) and pruritus (–1·6 pts, –2·1 to –1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity.
In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome.
Mirum Pharmaceuticals.
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease for which there is currently no pharmacologic therapy approved by the US Food and Drug Administration.
In this double-blind, ...placebo-controlled, phase 3 trial, patients 11–55 years of age with EoE and dysphagia were randomized 2:1 to receive budesonide oral suspension (BOS) 2.0 mg twice daily or placebo for 12 weeks at academic or community care practices. Co-primary endpoints were the proportion of stringent histologic responders (≤6 eosinophils/high-power field) or dysphagia symptom responders (≥30% reduction in Dysphagia Symptom Questionnaire DSQ score) over 12 weeks. Changes in DSQ score (key secondary endpoint) and EoE Endoscopic Reference Score (EREFS) (secondary endpoint) from baseline to week 12, and safety parameters were examined.
Overall, 318 patients (BOS, n = 213; placebo, n = 105) were randomized and received ≥1 dose of study treatment. More BOS-treated than placebo-treated patients achieved a stringent histologic response (53.1% vs 1.0%; Δ52% 95% confidence interval (CI), 43.3%–59.1%; P < .001) or symptom response (52.6% vs 39.1%; Δ13% 95% CI, 1.6%–24.3%; P = .024) over 12 weeks. BOS-treated patients also had greater improvements in least-squares mean DSQ scores and EREFS over 12 weeks than placebo-treated patients: DSQ, –13.0 (SEM 1.2) vs –9.1 (SEM 1.5) (Δ–3.9 95% CI, –7.1 to –0.8; P = .015); EREFS, –4.0 (SEM 0.3) vs –2.2 (SEM 0.4) (Δ–1.8 95% CI, –2.6 to –1.1; P < .001). BOS was well tolerated; most adverse events were mild or moderate in severity.
In patients with EoE, BOS 2.0 mg twice daily was superior to placebo in improving histologic, symptomatic, and endoscopic outcomes over 12 weeks. BOS 2.0 mg twice daily was well tolerated. ClinicalTrials.gov number: NCT02605837.
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The pharmacokinetic (PK) profile of budesonide oral suspension (BOS) was evaluated during a phase 2, randomized, double‐blind, placebo‐controlled, dose‐ranging study in pediatric patients with ...eosinophilic esophagitis (EoE) (MPI 101‐01/NCT00762073).
Non‐compartmental methods were used to calculate PK parameters in 37 patients after receiving morning doses of BOS, with volume and dose adjusted for age (low dose: 0.35 or 0.5 mg; high dose: 1.4 or 2.0 mg 2–9 or 10–18 years old, respectively). Relationships between apparent oral clearance and volume of distribution, and bodyweight and body mass index were also evaluated.
Budesonide systemic exposure increased with BOS dose. After oral administration, time to maximum plasma budesonide concentration occurred ~1 hour post dose and the half‐life of budesonide was 3.3–3.5 hours. PK parameters were similar between age groups for low‐ and high‐dose BOS, indicating that volume and dose adjustments for age were appropriate for pediatric patients with EoE. BOS was well tolerated.
Summary
Background
Questions remain regarding the safety of swallowed topical corticosteroids in eosinophilic oesophagitis (EoE).
Aim
To assess the safety of an investigational formulation of ...budesonide (budesonide oral suspension; BOS) from six trials.
Methods
Safety data were integrated from six trials (healthy adults: SHP621‐101 phase 1; patients with EoE: MPI 101‐01 and MPI 101‐06 phase 2; SHP621‐301, SHP621‐302 and SHP621‐303 phase 3) for participants who received ≥1 dose of study drug (BOS 2.0 mg twice daily b.i.d., BOS any dose including BOS 2.0 mg b.i.d. and placebo). Adverse events (AEs), laboratory testing, bone density and adrenal AEs were assessed. Exposure‐adjusted incidence rates were calculated for AEs and AEs of special interest (AESIs).
Results
Overall, 514 unique participants were included (BOS 2.0 mg b.i.d., n = 292; BOS any dose, n = 448; placebo, n = 168). The BOS 2.0 mg b.i.d., BOS any dose and placebo groups totalled 93.7, 122.4 and 25.0 participant‐years of exposure (PY), respectively. Proportions of treatment‐emergent AEs (TEAEs) and AESIs (any) reported were higher for BOS than placebo; however, most were mild/moderate in severity. The most commonly reported AESIs (exposure‐adjusted incidence rates per 100 PY) in the BOS 2.0 mg b.i.d., BOS any dose and placebo groups were infections (133.5, 154.4 and 136.2, respectively) and gastrointestinal AEs (84.3, 80.9 and 92.1, respectively). Adrenal AEs were more frequent with BOS 2.0 mg b.i.d. and BOS any dose than placebo (44.8, 34.3 and 24.0, respectively). TEAEs and AESIs related to study drug or leading to discontinuation were infrequent.
Conclusions
BOS was well‐tolerated; most TEAEs with BOS were mild/moderate in severity.
ClinicalTrials.gov numbers
SHP621‐101 (no clinical trials registration number), MPI 101‐01 (NCT00762073), MPI 101‐06 (NCT01642212), SHP621‐301 (NCT02605837), SHP621‐302 (NCT02736409) and SHP621‐303 (NCT03245840).
•Trends in use of bariatric procedure for adolescence were estimated. •Differences in weight loss by procedure at 1, 3, and 5 years were compared. •Gastric bypass and sleeve resulted in comparable ...BMI reduction. •AGB was markedly less effective.
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Bariatric surgery has been used for treatment of severe obesity in adolescents but most studies have been small and limited in follow-up.
We hypothesized that electronic health record data could be used to compare effectiveness of bariatric procedures in adolescents.
Data were obtained from clinical research networks using a common data model to extract data from each site.
Adolescents who underwent a primary bariatric procedure from 2005 through 2015 were identified. The percent change in body mass index (BMI) at 1, 3, and 5 years was estimated using random effects linear regression for patients undergoing all operations. Propensity score adjusted estimates and 95% confidence intervals were estimated for procedures with >25 patients at each time period.
This cohort of 544 adolescents was predominantly female (79%) and White (66%), with mean (±standard deviation) age of 17.3 (±1.6) years and mean BMI of 49.8 (± 7.8) kg/m2. Procedures included Roux-en-Y gastric bypass (RYGB; n = 177), sleeve gastrectomy (SG; n = 306), and laparoscopic adjustable gastric banding (n = 61). For those undergoing RYGB, SG, and laparoscopic adjustable gastric banding, mean (95% confidence interval) BMI changes of −31% (−30% to −33%), −28% (−27% to −29%), and −10% (−8% to −12%), were estimated at 1 year. For RYGB and SG, BMI changes of −29% (−26% to −33%) and −25% (−22% to −28%) were estimated at 3 years.
Adolescents undergoing SG and RYGB experienced greater declines in BMI at 1- and 3-year follow-up time points, while laparoscopic adjustable gastric banding was significantly less effective for BMI reduction.
Children with progressive familial intrahepatic cholestasis, including bile salt export pump (BSEP) and familial intrahepatic cholestasis–associated protein 1 (FIC1) deficiencies, suffer debilitating ...cholestatic pruritus that adversely affects growth and quality of life (QoL). Reliance on surgical interventions, including liver transplantation, highlights the unmet therapeutic need. INDIGO was an open‐label, Phase 2, international, long‐term study to assess the efficacy and safety of maralixibat in children with FIC1 or BSEP deficiencies. Thirty‐three patients, ranging from 12 months to 18 years of age, were enrolled. Eight had FIC1 deficiency and 25 had BSEP deficiency. Of the latter, 6 had biallelic, protein truncating mutations (t)‐BSEP, and 19 had ≥ 1 nontruncating mutation (nt)‐BSEP. Patients received maralixibat 266 μg/kg orally, once daily, from baseline to Week 72, with twice‐daily dosing permitted from Week 72. Long‐term efficacy was determined at Week 240. Serum bile acid (sBA) response (reduction in sBAs of > 75% from baseline or concentrations <102.0 μmol/L) was achieved in 7 patients with nt‐BSEP, 6 during once‐daily dosing, and 1 after switching to twice‐daily dosing. sBA responders also demonstrated marked reductions in sBAs and pruritus, and increases in height, weight, and QoL. All sBA responders remained liver transplant–free after > 5 years. No patients with FIC1 deficiency or t‐BSEP deficiency met the sBA responder criteria during the study. Maralixibat was generally well‐tolerated throughout the study. Conclusion: Response to maralixibat was dependent on progressive familial intrahepatic cholestasis subtype, and 6 of 19 patients with nt‐BSEP experienced rapid and sustained reductions in sBA levels. The 7 responders survived with native liver and experienced clinically significant reductions in pruritus and meaningful improvements in growth and QoL. Maralixibat may represent a well‐tolerated alternative to surgical intervention.
The long‐term efficacy and safety of maralixibat (a minimally absorbed, selective inhibitor of the ileal bile acid transporter) was assessed in children with BSEP or FIC1 deficiencies. Rapid and sustained reductions in sBA levels were observed in a subset of patients with non‐truncating BSEP deficiency, leading to transplant‐free survival, as well as reductions in pruritus and meaningful improvements in growth and quality of life. Maralixibat can be considered as an effective, well‐tolerated, nonsurgical alternative to surgical biliary diversion in these patients.
Objectives:
The objective of this study was to evaluate the efficacy and safety of budesonide oral suspension (BOS) in adolescents with eosinophilic esophagitis (EoE).
Methods:
This post hoc analysis ...pooled data from two 12‐week, randomized, double‐blind, placebo‐controlled studies of BOS 2.0 mg twice daily (b.i.d.) (phase 2, NCT01642212; phase 3, NCT02605837) in patients aged 11–17 years with EoE and dysphagia. Efficacy endpoints included histologic (≤6, ≤1, and <15 eosinophils per high‐power field eos/hpf), dysphagia symptom (≥30% reduction in Dysphagia Symptom Questionnaire DSQ scores from baseline), and clinicopathologic (≤6 eos/hpf and ≥30% reduction in DSQ scores from baseline) responses at week 12. Change from baseline to week 12 in peak eosinophil counts, DSQ scores, EoE Histology Scoring System (EoEHSS) grade (severity) and stage (extent) total score ratios (TSRs), and total EoE Endoscopic Reference Scores (EREFS) were assessed. Safety outcomes were also examined.
Results:
Overall, 76 adolescents were included (BOS, n = 45; placebo, n = 31). Significantly more patients who received BOS than placebo achieved histologic responses (≤6 eos/hpf: 46.7% vs 6.5%; ≤1 eos/hpf: 42.2% vs 0.0%; <15 eos/hpf: 53.3% vs 9.7%; P < 0.001) and a clinicopathologic response (31.1% vs 3.2%; P = 0.003) at week 12. More BOS‐treated than placebo‐treated patients achieved a dysphagia symptom response at week 12 (68.9% vs 58.1%; not statistically significant P = 0.314). BOS‐treated patients had significantly greater reductions in EoEHSS grade and stage TSRs (P < 0.001) and total EREFS (P = 0.021) from baseline to week 12 than placebo‐treated patients. BOS was well tolerated, with no clinically meaningful differences in adverse events versus placebo.
Conclusions:
BOS 2.0 mg b.i.d. significantly improved most efficacy outcomes in adolescents with EoE versus placebo.
LINKED CONTENT
This article is linked to Hirano et al papers. To view these articles, visit https://doi.org/10.1111/apt.17430 and https://doi.org/10.1111/apt.17442.
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