Abstract. This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of a new chewable, rapidly-disintegrating mebendazole (MBZ) 500 mg tablet for Ascaris lumbricoides and Trichuris trichiura infection treatment. Pediatric patients (1–15 years; N = 295; from Ethiopia and Rwanda) excreting A. lumbricoides and/or T. trichiura eggs were enrolled. The study had a screening phase (3 days), a double-blind treatment phase (DBP, 19 days), and an open-label phase (OLP, 7 days). Patients received MBZ or placebo on day 1 of DBP and open-label MBZ on day 19 ± 2 after stool sample collection. Cure rates (primary endpoint), defined as species-specific egg count of 0 at the end of DBP, were significantly higher in the MBZ group than placebo for A. lumbricoides (83.7% [72/86; 95% CI: 74.2%; 90.8%] versus 11.1% [9/81; 95% CI: 5.2%; 20.1%], P < 0.001) and for T. trichiura (33.9% [42/124; 95% CI: 25.6%; 42.9%] versus 7.6% [9/119; 95% CI: 3.5%; 13.9%], P < 0.001). Egg reduction rates (secondary endpoint) were significantly higher in the MBZ group than placebo for A. lumbricoides (97.9% [95% CI: 94.4; 99.9] versus 19.2% [95% CI: −5.9; 41.5]; P < 0.001) and T. trichiura (59.7% [95% CI: 33.9; 78.8] versus 10.5% [95% CI: −16.8; 32.9]; P = 0.003). Treatment-emergent adverse events (TEAEs) in MBZ group occurred in 6.3% (9/144) of patients during DBP and 2.5% (7/278) during OLP. No deaths, serious TEAEs, or TEAEs leading to discontinuations were reported. A 500 mg chewable MBZ tablet was more efficacious than placebo for the treatment of A. lumbricoides and T. trichiura infections in pediatric patients, and no safety concerns were identified.

Background Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-beta-cyclodextrins (HP beta CD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HP beta CD.Methods In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HP beta CD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HP beta CD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HP beta CD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range.Findings Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HP beta CD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HP beta CD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC 8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC 8-72 after doses of 900 mg (p=0.0063) and 1200 mg (p=0.0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HP beta CD were increased about two fold (p=0.0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1.22, SEM 0.34 points per year compared with 2.92, SEM 0.27 points per year (p=0.0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0.0622), cognition (p=0.0040) and speech (p=0.0423).Interpretation Patients with NPC1 treated with intrathecal HP beta CD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HP beta CD.Funding National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson.

In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-β-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-β-CD for the benefit of the NPC patient community. Keywords: 2-hydroxypropyl-β-cyclodextrin, Niemann-Pick disease type C1, neurodegenerative rare disease, translational research.

In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-β-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-β-CD for the benefit of the NPC patient community.

Objective:The aim of the present study was to evaluate 24-week maintenance of efficacy and safety of rabeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD).Methods:Children ages 1 to 11 years who achieved endoscopic/histologic healing (defined as grade 0 of the Hetzel-Dent Classification scale and/or grade 0 of the Histological Features of Reflux Esophagitis scale) in a 12-week treatment phase were continued on the same dose for an additional 24 weeks during the maintenance phase. The dose was determined by weight: children weighing 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children weighing >= 15 kg (high-weight cohort) received 10 or 20 mg.Results:Healing was maintained in 90% of children (100% [low-weight cohort]; 89% [10 mg, high-weight cohort]; 85% [20 mg, high-weight cohort]). The Total GERD Symptom and Severity score continued to improve slightly in all of the children across all dose groups (P = 0.026) during the maintenance phase, except the 10-mg dose group (low-weight cohort), which experienced a slight worsening of 3.6 points. Overall, 71% children felt better on the GERD Symptom Relief score (P < 0.001); 95% of investigators and 92% of parent/caregivers rated "Good to Excellent" on the Global Treatment Satisfaction scale and Clinical Global Impressions Improvement scale, respectively. Overall incidence of treatment-emergent adverse events was 63%; upper respiratory tract infections (13%) and vomiting (11%) were the most commonly reported (>10%).Conclusions:Rabeprazole was effective in maintaining endoscopic/histologic healing during a 24-week maintenance period in children with endoscopically proven GERD. The clinical effect and safety profile were largely similar across dose groups.

OBJECTIVE:Evaluate the efficacy and safety of rabeprazole in children, 1 to 11 years old, with endoscopically/histologically proven gastroesophageal reflux disease (GERD). METHODS:Children were randomized to 0.5- or 1.0-mg/kg rabeprazole granule formulation for 12 weeks. The dose was further determined by weight: children 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children ≥15 kg (high-weight cohort) received 10 or 20 mg. The primary endpoint was endoscopic/histologic healing at week 12 (defined as grade 0 on the Hetzel-Dent classification scale and/or grade 0 on the Histological Features of Reflux Esophagitis scale). RESULTS:Overall, 81% (87/108) achieved endoscopic/histologic healing at week 12 with higher healing in the low-weight cohort (82% [5-mg dose], 94% [10-mg dose]) compared with high-weight cohort (76% [10-mg dose], 78% [20-mg dose]). There was a significant (P < 0.001) decrease in the mean Total GERD Symptoms and Severity score from 19.7 points (baseline) to 8.6 points (week 12), with 26% fewer children reporting GERD symptoms at week 12. The average frequency of symptoms per child decreased from 7.7 (week 1) to 4.7 (week 12). The GERD Symptom Relief score showed that 71% of children felt better, 81% were rated "good to excellent" on the Global Treatment Satisfaction scale by the investigator; 77% were rated "good to excellent" on the Clinical Global Impressions-Improvement scale by the parent/caregiver. The most common (>10%) treatment-emergent adverse events included cough and vomiting (14% each), abdominal pain (12%), and diarrhea (11%). CONCLUSIONS:Rabeprazole was effective and safe in 1- to 11-year-old children with GERD.

lasting >5 min showed a monotonic decline with increasing dose: placebo 3.8, naronapride 12 mg 2.9, naronapride 40 mg 2.1. The difference between placebo and naronapride 40 mg was significant (p=0.0007), as was the dose-response (p=0.0049). The mean duration of acid reflux episodes also showed some reduction with treatment: 0.67 min on placebo; 0.60 min on both naronapride 12 mg and 40 mg. The dose response was significant (p= 0.0057). Conclusions: Treatment with naronapride resulted in a consistent and dose-related decrease in several measures of esophageal acid exposure, including mean % of time with pH<4.0, total number of acid reflux episodes, the mean duration of acid reflux episodes and the number of acid reflux episodes over 5 min duration. Taken together, these findings suggest that naronapride may be effective in the treatment of acid reflux disorders, and further studies are warranted.

The authors regret that during the publication of the above paper Table 3 was published incorrectly, the heading on the right side of the table currently reads “Placebo (N=20)” which is incorrect it should read, “PANCREAZE® (N=20)”. Table 3 is reproduced correctly below:Table 3Other secondary efficacy and safety assessments of the participants.Assessment, n (%)Treatment groupPlacebo (N=20)PANCREAZE® (N=20)n (%)n (%)EPI symptomsaNumber (percent) of patients with ≥1 EPI symptom during treatment.Any11 (55)4 (20)Abdominal pain6 (30)3 (15)Bloating3 (15)1 (5)Diarrhea4 (20)0 (0)Greasy stools3 (15)0 (0)Vomiting0 (0)1 (5)Stool categorybReported at least one during treatment; hard, soft and watery or oily considered abnormal.Abnormal stool18 (90)15 (75)Hard0 (0)4 (20)Soft16 (80)13 (65)Watery or greasy14 (70)2 (10)GAC scorecResponse at end of study.Excellent0 (0)4 (20)Better2 (10)9 (45)Same11 (55)7 (35)Worse7 (35)0 (0)Treatment-emergent adverse eventsAny TEAE12 (60)8 (40)Treatment-related TEAE10 (50)4 (20)Most common TEAEdOccurring in ≥2 participants (≥10%) in either treatment group. Diarrhea4 (20)0 (0) Abdominal pain3 (15)2 (10) Abdominal pain upper3 (15)1 (5) Flatulence3 (15)1 (5) Abnormal feces3 (15)0 (0) Fatigue2 (10)0 (0)EPI: exocrine pancreatic insufficiency; GAC: global assessment of change; TEAE: treatment-emergent adverse event.a Number (percent) of patients with ≥1 EPI symptom during treatment.b Reported at least one during treatment; hard, soft and watery or oily considered abnormal.c Response at end of study.d Occurring in ≥2 participants (≥10%) in either treatment group. Open table in a new tab EPI: exocrine pancreatic insufficiency; GAC: global assessment of change; TEAE: treatment-emergent adverse event. The authors would like to apologise for any inconvenience this may have caused to the readers of the journal. Efficacy and safety of PANCREAZE® for treatment of exocrine pancreatic insufficiency due to cystic fibrosisJournal of Cystic FibrosisVol. 10Issue 5PreviewPancreatic enzyme replacement therapy (PERT) is critical for correction of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF). Full-Text PDF Open Archive

lasting >5 min showed a monotonic decline with increasing dose: placebo 3.8, naronapride 12 mg 2.9, naronapride 40 mg 2.1. The difference between placebo and naronapride 40 mg was significant (p=0.0007), as was the dose-response (p=0.0049). The mean duration of acid reflux episodes also showed some reduction with treatment: 0.67 min on placebo; 0.60 min on both naronapride 12 mg and 40 mg. The dose response was significant (p= 0.0057). Conclusions: Treatment with naronapride resulted in a consistent and dose-related decrease in several measures of esophageal acid exposure, including mean % of time with pH<4.0, total number of acid reflux episodes, the mean duration of acid reflux episodes and the number of acid reflux episodes over 5 min duration. Taken together, these findings suggest that naronapride may be effective in the treatment of acid reflux disorders, and further studies are warranted.

BackgroundPancreatic enzyme replacement therapy (PERT) is critical for correction of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF).MethodsThis was a randomized, placebo-controlled PERT withdrawal study evaluating the efficacy and safety of PANCREAZE® (pancrelipase) in CF patients with EPI. Participants (n=49) entered an open-label, ≤14day run-in phase, maintained a high-fat diet (100±15g/day), and received PANCREAZE® (10.5 or 21). Participants with a coefficient of fat absorption (CFA)≥80% (n=40) were then randomized (1:1) to receive either PANCREAZE® or placebo during a double-blind, ≤7day withdrawal phase.ResultsPANCREAZE® improved fat absorption as shown by significantly lower mean±SD change in CFA between open-label and double-blind phases for PANCREAZE® (−1.5±5.88%; p<0.001) compared to placebo (−34.1±23.03%). Protein absorption was similarly improved. No unexpected adverse events were reported.ConclusionsThis study demonstrated PANCREAZE® was effective in treating EPI due to CF and was safe and well tolerated.