Long-term administration of intravenous Trappsol® Cyclo™ (HP-ß-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial.

Background: Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed a critical role of systemically administered hydroxypropyl-ß-cyclodextrin (HP-ß-CD; Trappsol® Cyclo™) in cholesterol metabolism and homeostasis in peripheral tissues of the body, including the liver, and in the central nervous system (CNS). Herein, the pharmacokinetics (PK), safety, and efficacy of HP-ß-CD, and biomarkers of NPC were assessed in pediatric and adult patients with NPC1. Methods: This was a multicenter, Phase I/II, randomized, double-blind, parallel-group, 48-week study (ClinicalTrials.gov identifier NCT02912793) to compare the PK of three different single intravenous (IV) doses of HP-ß-CD in pediatric and adult patients with NPC1 and to evaluate the efficacy and tolerability of three different dosages of HP-ß-CD in patients with NPC1 after long-term treatment. Twelve patients aged at least 2 years (2-39 years of age) with a confirmed diagnosis of NPC1 were randomized to receive one of three IV doses of HP-ß-CD (1500 mg/kg, 2000 mg/kg, or 2500 mg/kg) every 2 weeks for 48 weeks. All patients received HP-ß-CD; there was no placebo or other control. PK testing of plasma and cerebrospinal fluid (CSF) was at set times after the first infusion. Pharmacodynamic assessments included biomarkers of cholesterol metabolism (synthesis and breakdown products), N-palmitoyl-O-phosphocholineserine (PPCS), and specific biomarkers of CSF neurodegeneration (including total Tau), CNS inflammation (glial fibrillary acidic protein [GFAP] and tumor necrosis factor α [TNFα]), CNS cholesterol metabolism (24S-hydroxycholesterol) and inflammatory markers. Efficacy measures included clinical disease severity, neurologic symptoms, and clinical impressions of improvement. Safety assessment included physical examination, vital signs, clinical safety laboratory assessment and adverse events (AEs). Results: Nine patients completed the study, 2 in the 1500 mg/kg group, 4 in the 2000 mg/kg group and 3 in the 2500 mg/kg group. Three patients (all in the 1500 mg/kg group) discontinued the study because of either physician decision/site Principal Investigator (PI) discretion, withdrawal by subject/patient/parent/guardian, or other non-safety reasons. In 5 patients who underwent serial lumbar punctures, HP-ß-CD was detected in the CSF. Of the 9 patients who completed the study, 8 (88.9%) improved in at least two domains of the 17-Domain Niemann-Pick disease Type C-Clinical Severity Scale (17D-NPC-CSS), and 6 of these patients improved in at least one domain viewed by patients and their caregivers to be key to quality of life, namely, speech, swallow, fine and gross motor skills, and cognition. Of the 9 patients who completed the study, 7 were viewed by their treating physicians as having improved to some degree at the end of the study, and 2 remained stable; both outcomes are highly relevant in a progressive neurodegenerative disease. Some patients and families reported improvement in quality of life.All three doses of HP-ß-CD were well tolerated overall, with most treatment-emergent adverse events transient, mild-to-moderate in nature, and considered by the site PIs to be not related to study drug. Interpretation: This 48-week trial is the longest to date to evaluate the safety, tolerability, and efficacy across multiple clinical endpoints of IV administration of Trappsol® Cyclo™ (HP-ß-CD) in NPC1 patients. In pediatric and adult patients with NPC, Trappsol® Cyclo™ IV improved clinical signs and symptoms and was generally well tolerated. The findings presented here demonstrate a favorable benefit-risk profile and support the global pivotal trial now underway to evaluate the long-term treatment benefits and the potential of Trappsol® Cyclo™ as a disease-modifying treatment in this patient population.

Intravenous 2-hydroxypropyl-ß-cyclodextrin (Trappsol® Cyclo™) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial.

BACKGROUND: Niemann-Pick Disease Type C1 (NPC1) is a disorder of intracellular cholesterol and lipid trafficking that leads to the accumulation of cholesterol and lipids in the late endosomal/lysosomal compartment, resulting in systemic manifestations (including hepatosplenomegaly and lung infiltration) and neurodegeneration. Preclinical studies have demonstrated that systemically administered 2-hydroxypropyl-ß-cyclodextrin (HPßCD; Trappsol® Cyclo™) restores cholesterol metabolism and homeostasis in peripheral organs and tissues and in the central nervous system (CNS). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of HPßCD in peripheral tissues and the CNS in adult subjects with NPC1. METHODS: A Phase 1, randomized, double-blind, parallel group study enrolled 13 subjects with NPC1 who received either 1500 mg/kg or 2500 mg/kg HPßCD intravenously every 2 weeks for a total of 7 doses (14 weeks). Subjects were 18 years or older, with a confirmed diagnosis of NPC1 and evidence of systemic involvement on clinical assessment. Pharmacokinetic evaluations in plasma and cerebrospinal fluid (CSF) were performed at the first and seventh infusions. Pharmacodynamic assessments included biomarkers of systemic cholesterol synthesis (serum lathosterol) and degradation (serum 4ß-hydroxycholesterol), secondary sphingomyelin storage (plasma lysosphingomyelin-509, now more accurately referred to as N-palmitoyl-O-phosphocholineserine [PPCS]), and CNS-specific biomarkers of neurodegeneration (CSF total Tau) and cholesterol metabolism (serum 24(S)-hydroxycholesterol [24(S)-HC]). Safety monitoring included assessments of liver and kidney function, infusion related adverse events, and hearing evaluations. RESULTS: Ten subjects completed the study, with 6 at the 1500 mg/kg dose and 4 at the 2500 mg/kg dose. One subject withdrew following the first infusion after experiencing hypersensitivity pneumonitis, and 2 subjects withdrew after meeting a stopping rule related to hearing loss. Overall, HPßCD had an acceptable safety profile. The observed pharmacokinetic profile of HPßCD was similar following the first and seventh infusions, with a plasma half-life of 2 h, a maximum concentration reached at 6 to 8 h, and no evidence of accumulation. Serum biomarkers of cholesterol metabolism showed reduced synthesis and increased degradation. Compared to Baseline, filipin staining of liver tissue showed significant reductions of trapped unesterified cholesterol at both dose levels at Week 14. Plasma PPCS levels were also reduced. HPßCD was detected at low concentrations in the CSF (maximum, 33 µM) at both dose levels and persisted longer in CSF than in plasma. Total Tau levels in CSF decreased in most subjects. Serum levels of 24(S)-HC, a cholesterol metabolite from the CNS that is exported across the blood-brain barrier and into the circulation, decreased after both the first and seventh doses. Hence, pharmacodynamic assessments in both peripheral and CNS-related tissue show target engagement. While not the aim of the study, subjects reported favorable impacts on their quality of life. CONCLUSIONS: The plasma pharmacokinetics and pharmacodynamics of HPßCD administered at two intravenous dose levels to subjects with NPC1 were comparable to those observed in preclinical models. HPßCD cleared cholesterol from the liver and improved peripheral biomarkers of cholesterol homeostasis. At low CSF concentrations, HPßCD appeared to be pharmacologically active in the CNS based on the increased efflux of 24(S)-HC and reduction in CSF total Tau, a biomarker of CNS neurodegeneration. These data support the initiation of longer-term clinical trials to evaluate the safety and efficacy of intravenous HPßCD in subjects with NPC1. (ClinicalTrials.gov numbers: present trial, NCT02939547; open-label extension of the present trial, NCT03893071; global pivotal trial, NCT04860960).

Expanded access with intravenous hydroxypropyl-ß-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis.

BACKGROUND: Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPßPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPßCD has been administered to NPC patients with approved INDs globally since 2009. RESULTS: Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPßCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPßCD following on average 13 months of IV HPßCD. Several patients transitioned to an alternate HPßCD. Moderately affected NPC patients treated with HPßCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. CONCLUSIONS: These expanded access data support the safety and potential benefit of systemic IV administration of HPßCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPßCD in NPC patients.

The Global Virus Network: Challenging chikungunya.

The recent spread of chikungunya virus to the Western Hemisphere, together with the ongoing Ebola epidemic in West Africa, have highlighted the importance of international collaboration in the detection and management of disease outbreaks. In response to this need, the Global Virus Network (GVN) was formed in 2011. The GVN is a coalition of leading medical virologists in 34 affiliated laboratories in 24 countries, who collaborate to share their resources and expertise. The GVN supports research, promotes training for young scientists, serves as a technical resource for governments, businesses and international organizations, facilitates international scientific cooperation, and advocates for funding and evidence-based public policies. In response to the spread of chikungunya, the GVN formed a task force to identify research gaps and opportunities, including models of infection and disease, candidate vaccines and antivirals, epidemiology and vector control measures. Its members also serve as authoritative sources of information for the public, press, and policy-makers. This article forms part of a symposium in Antiviral Research on "Chikungunya discovers the New World".

Building global environmental health capacity through international scientific cooperation and partnerships.

Sponsored by the Fogarty International Center, the NIEHS, and NIOSH, the International Training and Research Program in Environmental and Occupational Health (ITREOH) supports training of health professionals worldwide. The program grants awards to U.S. academic institutions, which partner with institutions in low- and middle-income countries to address health threats of regional importance.

Response to: "Rescuing the NIH before it is too late".

We, the directors of the 27 NIH institutes and centers, wanted to respond to the points made by Andrew Marks in his recent editorial. While we appreciate that the scientific community has concerns, the current initiatives and directions of the NIH have been developed through planning processes that reflect openness and continued constituency input, all aimed at assessing scientific opportunities and addressing public health needs.

A case for developing North-South partnerships for research in sickle cell disease.

For a better understanding of the pathophysiology and mechanisms of phenotypic diversity of sickle cell disease, and for the improvement of its management globally, there is a strong case for developing sustainable research partnerships between rich and poor countries.

Addressing the growing burden of trauma and injury in low- and middle-income countries.

Low- and middle-income countries suffer disproportionately from reduced life expectancy and quality of life. Injuries are overlooked as contributors to global inequities in health, yet the long-term disabilities they frequently produce represent a significant burden. The Fogarty International Center of the National Institutes of Health convened a panel of experts in trauma and injury from the United States and low- and middle-income nations to identify research gaps in this area and opportunities to create new knowledge. Panel members identified sustainable programs of research established through stable linkages between institutions in high-income nations and those in low- and middle-income nations as a priority. The resulting benefits of addressing the growing burden of trauma and injury to communities in resource-constrained settings around the world would be substantial.

Paradigms and progress in building research capacity in international environmental health.

Populations in low- and middle-income nations bear significant risks for poor health due to air, land and water contamination; natural resource depletion; deterioration of ecosystems; contaminated food supplies and other conditions related to poverty, including poor housing, crowding and inadequate nutrition and health care. These risks, related to rapid industrialization, increasing urbanization, poor land use, natural changes in ecology and other conditions, will only increase in the coming decades if current trends persist. The implications on populations' health include increased spread or emergence of disease, particularly those that impact children disproportionately, and added stress on already overburdened or weakened health care systems. To address environmental health conditions in a relevant manner in resource-poor settings, the training of scientists and health professionals from these settings is key to setting priorities and identifying cost-effective interventions. Training of professionals in a range of environmental health disciplines is a prerequisite for the establishment of effective national and international policies. Working to strengthen local expertise and scientific capacity is one of the most effective and lasting ways to affect positive policy change in environmental health. This paper describes four paradigms that support research training and research programs to meet the increasing and changing needs in this field. Factors influencing the development of the programs and their evolution are discussed as well as trends for the future.