Gail M. Comer

Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study

Objective Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC. Design In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels. Results The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups. Conclusions A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13. Trial registration number ClinicalTrials.gov number NCT01284062.

Efficacy and safety of pantoprazole delayed-release granules for oral suspension in a placebo-controlled treatment-withdrawal study in infants 1-11 months old with symptomatic GERD.

Objective: The objective of this study was to assess the efficacy of pantoprazole in infants with gastroesophageal reflux disease (GERD). Materials and Methods: Infants ages 1 through 11 months with GERD symptoms after 2 weeks of conservative treatment received open-label (OL) pantoprazole 1.2 mg · kg−1 · day−1 for 4 weeks followed by a 4-week randomized, double-blind (DB), placebo-controlled, withdrawal phase. The primary endpoint was withdrawal due to lack of efficacy in the DB phase. Mean weekly GERD symptom scores (WGSSs) were calculated from daily assessments of 5 GERD symptoms. Safety was assessed. Results: One hundred twenty-eight patients entered OL treatment, and 106 made up the DB modified intent-to-treat population. Mean age was 5.1 months (82% full-term, 64% male). One third of patients had a GERD diagnostic test before OL study entry. WGSSs at week 4 were similar between groups. WGSSs decreased significantly from baseline during OL therapy (P < 0.001), when all patients received pantoprazole. The decrease in WGSSs was maintained during the DB phase in both treatment groups. There was no difference in withdrawal rates due to lack of efficacy (pantoprazole 6/52; placebo 6/54) or time to withdrawal during the DB phase. The greatest between-group difference in WGSS was slightly worse with placebo at week 5 (P = 0.09), mainly due to episodes of arching back (P = 0.028). No between-group differences in adverse event frequency were noted. Serious adverse events in 8 patients were considered unrelated to treatment. Conclusions: Pantoprazole significantly improved GERD symptom scores and was well tolerated. However, during the DB treatment phase, there were no significant differences noted between pantoprazole and placebo in withdrawal rates due to lack of efficacy.

Multicenter, Randomized, Double-Blind Study Comparing 20 and 40 mg of Pantoprazole for Symptom Relief in Adolescents (12 to 16 Years of Age) with Gastroesophageal Reflux Disease (GERD)

An age-appropriate questionnaire (GASP-Q) was used to assess the frequency and severity of the gastroesophageal reflux disease (GERD) symptoms: abdominal/belly pain, chest pain/heartburn, pain after eating, nausea, burping/belching, vomiting/regurgitation, choking when eating, and difficulty swallowing, in adolescents age 12 to 16 years. The primary objective was to compare the mean composite symptom score (CSS) at week 8 with baseline after treatment with 20 or 40 mg of pantoprazole. Statistically significant (p < 0.001) improvement in CSS occurred in both groups. Safety was comparable between the 2 groups. Pantoprazole was safe, well tolerated, and effective in reducing symptoms of GERD in adolescents.

Anti-IL21 receptor monoclonal antibody (ATR-107): Safety, pharmacokinetics, and pharmacodynamic evaluation in healthy volunteers: a phase I, first-in-human study.

Safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ATR‐107, a fully human monoclonal anti‐IL‐21 receptor (IL‐21R) antibody, administered as ascending single doses, subcutaneously or intravenously, was evaluated in a placebo‐controlled, double‐blind trial in healthy subjects. The dose levels were 3–300 mg by SC and 30–120 mg by IV. The most important adverse events were hypersensitivity reactions occurring in three out of six subjects in 300 mg SC cohort and considered as dose limiting toxicity. More than 75% of the subjects who received ATR‐107 developed anti‐drug antibodies (ADAs), which had no discernible impact on PK or safety. The PK of ATR‐107 appeared to be dose ‐proportional. T1/2 was shorter than typical therapeutic antibodies. Bioavailability of ATR‐107 was about 30%. IL‐21R occupancy was measured in circulating B cells in the 60 and 120 mg IV cohort. The data indicated that single dose of ATR‐107 was able to maximally occupy IL‐21Rs through at least Day 42. Further escalation in the FIH study was halted partially due to the high rates of ADA formation. In conclusion, ATR‐107 had a prolonged PD effect measured by IL‐21R occupancy; was highly immunogenic after single dose administration and had PK properties with rapid clearance and low bioavailability.

Effect of Oral Supplementation on Catch-Up Growth in Picky Eaters

Ninety-two subjects ages 36 to 60 months who had picky-eater behavior and evidence of growth faltering were randomized to receive either nutrition counseling alone, or nutrition counseling plus a nutritional supplement (Study) for 90 days. The Study group had significantly greater increases in weight and height. There were no significant differences between groups in changes in appetite or activity levels, or in gastrointestinal symptom scores. The percent of subjects who developed upper respiratory tract infections was significantly lower in the Study group. These data suggest that a nutritional supplement in addition to nutrition counseling promote catch-up growth and may contribute to lower rates of infectious disease in children with picky eater behavior.

A Multicenter, Randomized, Open‐Label, Pharmacokinetics and Safety Study of Pantoprazole Tablets in Children and Adolescents Aged 6 Through 16 Years With Gastroesophageal Reflux Disease

Children with gastroesophageal reflux disease (GERD) may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drugs kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed‐release tablets in pediatric patients with GERD aged 6 to 11 years (study 1) and 12 to 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar to PK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug‐associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed‐release tablets can be used to provide systemic exposure similar to that in adults.

Clinical Results From a Randomized, Double-Blind, Dose-Ranging Study of Pantoprazole in Children Aged 1 Through 5 Years With Symptomatic Histologic or Erosive Esophagitis

In an 8-week, multicenter, randomized, double-blind study, we evaluated the efficacy and tolerability of pantoprazole (0.3mg/kg [low dose (LD)], 0.6 mg/kg [medium dose (MD)], and 1.2 mg/kg [high dose (HD)]) for delayed-release oral suspension (granules) in patients 1 to 5 years with documented symptoms of gastroesophageal reflux disease (GERD) and endoscopic evidence of reflux-related erosive esophagitis (EE) or histologic esophagitis (HE) consistent with GERD. Patients with HE were randomly assigned to LD, MD, or HD, and patients with EE, to MD or HD. A daily eDiary captured 5 individual GERD symptoms. A total of 60 patients (56 HE, 4 EE) were randomized. Mean weekly GERD symptom score (WGSS, sum of weekly mean frequency scores for 5 individual GERD symptoms) for the modified intention-to-treat HE population at the final week was improved with LD ( P < .001), MD (P = .063), and HD (P < 0.001) (paired t-tests). Patients with EE were healed at week 8. Adverse event incidences did not increase with dose.

Randomized, open-label, multicentre pharmacokinetic studies of two dose levels of pantoprazole granules in infants and children aged 1 month through <6 years with gastro-oesophageal reflux disease.

AbstractBackground and Objective: The primary objective of this study was to characterize the pharmacokinetic profile of pantoprazole delayed-release granules in infants and children aged 1 month to <6 years with gastro-oesophageal reflux disease (GORD). The studies described in this manuscript were conducted to fulfil the requirements of the paediatric written request for pantoprazole by the US FDA. Methods: Two randomized, open-label, multicentre studies were conducted in infants aged 1 month to <12 months (study 1) and children aged 1 year through <6 years (study 2) with GORD. Patients were randomly assigned to either the low-dose pantoprazole group (0.6mg/kg equivalent) or the high-dose pantoprazole group (1.2mg/kg equivalent) in a 1:1 fashion. Pantoprazole granules were administered approximately 30 minutes before breakfast for at least five consecutive doses. Blood samples were obtained at prespecified intervals. Plasma pantoprazole concentration-time data were analysed by non-compartmental methods. Descriptive statistics were calculated for pharmacokinetic parameters. Patients in study 2 additionally received pantoprazole for 28 days. Safety was monitored throughout. Results: In study 1, 43 patients were randomized; 42 were included in the single-dose pharmacokinetic evaluation (15 females, 27 males; mean postnatal age 6.3 months). In study 2,17 patients were randomized, and all were included in the single-dose pharmacokinetic evaluation (6 females, 11 males; mean age 3.2 years). In both studies, exposure increased with dose. Mean (standard deviation) maximum (peak) plasma concentration values for the low and high doses were 503 (506) ng/mL and 1318 (1307) ng/mL, respectively, in study 1, and 229 (196) ng/mL and 653 (645) ng/mL, respectively, in study 2. Area under the plasma concentration-time curve values for the low and high doses were 1046 (1043) ngh/mL and 3602 (3269) ng • h/mL, respectively, in study 1, and 293 (146) ng • h/mL and 2448 (2170) ng • h/mL, respectively, in study 2. There was a trend for increasing clearance with increasing age across the ages 1 month through <6 years. There was no evidence of drug accumulation after multiple doses. On-treatment adverse events (AEs) occurred in 19 of 43 patients in study 1 and in 11 of 17 patients in study 2. Serious AEs occurred in two patients in study 1 (gastroenteritis in one patient and acute gastroenteritis from rota virus infection resulting in discontinuation of one patient); the serious AEs resolved and were not considered by the investigators to be drug related. No other safety-related discontinuations occurred in either study. Conclusions: Exposure increased with increasing doses of pantoprazole granules, even though wide inter-individual variability was observed. Compared with that in adults receiving pantoprazole 40 mg, exposure obtained with the 1.2 mg/kg dose was similar in study 1 and slightly lower in study 2. Pantoprazole was generally well tolerated in infants and children aged 1 month through <6 years with GORD.

Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II)

Objective Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn’s disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported. Design Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up. Results 247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn’s Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis. Conclusions PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development. Trial registration number NCT01287897 and NCT01345318.

P516 Discrepancy between fecal biomarkers and their intestinal gene expression in ulcerative colitis: Results from an anti-IL-13 antibody study

Methods: A questionnaire about disease (type, localization, diagnosis, treatment and surveillance) was distributed to IBD patients who attended outpatient gastroenterology clinic at our Hospital. The answers were categorized as appropriate or inappropriate. Demographic data, education level and features of the disease were recorded. Results: 73 patients were included (41 females) with a mean age of 44 years-old and a mean duration of IBD of 9.4 years. There were 42 patients with Ulcerative Colitis, 29 with Crohn’s disease and 2 with unclassified IBD. The mean of appropriate answers was 53.6%. The type of IBD was correctly marked in 86% of patients whereas the specific localization of the disease was recognized in only 27%. 95% of the responders considered colonoscopy important in diagnosis. Only 55% of the patients were aware of the increased risk of bowel cancer. A better performance in the questionnaire was associated with: younger patients at diagnosis (r = 0.593; p = 0.000) and at the time of the questionnaire (r = 0.451; p = 0.000), a higher education level (F = 5.976; p = 0.001), presence of Crohn’s Disease (65% versus 46%, F = 6.990; p = 0.000), previous hospitalization (60% versus 42%, t = 4.197; p = 0.000) or surgery related to the disease (66% vs 51%, t = 2.401; p = 0.019) and multiple past medications (including 2 anti-tumor necrosis factor therapy) (F = 4.194; p = 0.000). Conclusions: The age, the educational level of the patient and the severity of the disease requiring hospitalization, surgery or aggressive therapy, were associated with a better knowledge of the disease. The low percentage (marginally positive) of appropriate responses highlights the need for better educational strategies.