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Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a rare autosomal recessive lysosomal disorder characterized by deficient heparan-N-sulfatase (HNS) activity, and subsequent accumulation of heparan sulfate, especially in the central nervous system. The disease is associated with progressive neurodegeneration in early childhood. For this open-label extension study of a phase 2b clinical trial, we report on safety and cognitive decline in patients receiving intrathecal (IT) administration of recombinant human HNS (rhHNS). Of 21 patients who completed the phase 2b study, 17 continued in the open-label extension. Patients receiving rhHNS IT 45 mg continued to receive the same treatment regimen (i.e., every 2 weeks or every 4 weeks) throughout the extension. Patients receiving no treatment in the phase 2b study were re-randomized to the treatment groups. Neurocognition was assessed using the Bayley Scales of Infant and Toddler Development®, Third Edition (BSID-III). Adverse events were recorded over the duration of the treatment period. Cognitive decline was observed in most patients in both treatment groups; however, improvements in BSID-III development quotient score were observed for two patients, in receptive and expressive communication scores for three patients each, in fine motor skills for one patient, and in gross motor skills for six patients. Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. The extension study was terminated early as the primary endpoints of the phase 2b study were not met, and no statistical analyses were carried out. Although cognitive decline was apparent in most patients, improvements were observed in a small group of patients. Greater declines were observed in patients at the higher end of the age range, suggesting earlier intervention may increase the possibility of a response to treatment. rhHNS IT treatment remained generally well tolerated up to 96 weeks.

Background Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial. Methods Twenty-one patients, randomized 1:1:1 to rhHNS IT 45 mg administered every 2 weeks (Q2W), every 4 weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. The primary efficacy goal was defined as ≤10-point decline (responder) in at least three patients in a dosing cohort after 48 weeks. Other efficacy assessments included adaptive behavioral function, assessments of cortical gray matter volume, and glycosaminoglycan (GAG) levels in urine. Results A clinical response to rhHNS IT was observed in three treated patients (two in the Q2W group, one in the Q4W group). Cerebrospinal fluid heparan sulfate and urine GAG levels were reduced in all treated patients. However, most secondary efficacy assessments were similar between treated patients (n = 14; age, 17.8–47.8 months) and untreated controls (n = 7; age, 12.6–45.0 months). Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. Conclusion rhHNS IT treatment reduced heparan sulfate and GAG levels in treated patients. Though the primary neurocognitive endpoint was not met, important lessons in the design and endpoints for evaluation of cognitive and behavioral diseases resulted. Trial registration ClinicalTrials.gov NCT02060526 ; EudraCT 2013-003450-24.

Introduction Currently, there is no effective therapy for mucopolysaccharidosis IIIA (MPS IIIA). Intravenously-administered enzyme replacement therapies, while effective in other forms of MPS without neurological involvement, have not been successful in patients with MPS IIIA, as they are unable to cross the blood-brain barrier to improve neurological symptoms. We evaluated the long-term safety, tolerability, and clinical outcomes of recombinant human heparan-N-sulfatase (rhHNS) administered intrathecally (IT) in children with MPS IIIA in a phase 1/2 extension study. Methods Patients aged ≥3 years with MPS IIIA who had previously completed a phase 1/2 study and received ≥5 of the 6 planned rhHNS infusions via IT administration, were eligible for inclusion. Patients who received 10 mg in the phase 1/2 study had their dose increased to 45 mg. Patients who were treated with 45 mg or 90 mg rhHNS IT in the phase 1/2 study remained on this monthly dose in the extension study. rhHNS was administered via an intrathecal drug delivery device (IDDD). Primary endpoints included the type and severity of adverse events, presence of anti-rhHNS antibodies in the CSF and serum, and changes in laboratory values. Secondary endpoints included standardized neurocognitive assessments and brain magnetic resonance imaging. Results In the extension study, 12 patients with a mean (SD) age of 9.6 (7.3) years continued treatment with rhHNS IT for a median of 264.4 weeks. Ten of 12 patients completed the extension study. rhHNS IT was generally well-tolerated. All patients experienced at least one treatment-emergent adverse event (TEAE), most being mild or moderate in severity. No serious adverse events (SAEs) were considered related to the study drug, and no deaths occurred. Most SAEs were related to malfunctions of the IDDD. Declines from baseline in Bayley Scales of Infant Development, Third Edition or Kaufman Assessment Battery for Children, Second Edition, Nonverbal Index developmental quotient scores were evident at all rhHNS dosing groups: -17.97%, -18.99%, and -12.12% in the 10/45, 45, and 90 mg groups, respectively, at Month 54. Conclusions Overall, rhHNS IT was well tolerated in the extension study. However, rhHNS IT was unable to slow the neurocognitive decline of patients with MPS IIIA. This study was subsequently terminated early because pre-specified efficacy criteria were not met, and the study did not yield clinical proof of concept. (Clinicaltrials.gov Identifier NCT01299727).

Two-thirds of patients with mucopolysaccharidosis type II (MPS II Hunter syndrome), a rare lysosomal disease characterized by iduronate-2-sulfatase deficiency, have cognitive impairment. This observational, prospective, longitudinal study (NCT01822184) assessed cognitive status and adaptive behavior in patients aged 2− 70 (n=26) were −2.4 (p=0.5657) at month 12 and −7.4 (p=0.1461) at month 24. Similarly, for VABS-II ABC scores, differences in LSM changes from baseline between the GCA subgroups (≤70/>70) were −1.9 (p=0.5545) at month 12 and 0.3 (p=0.9484) at month 24. Overall, cognitive ability and adaptive behavior in the pediatric MPS II population who completed this study remained relatively stable over 24 months. However, some patients experienced a rapid decline in cognitive ability, while others retained stable, but impaired, cognitive function. Shire funded this study and medical writing support.

To evaluate the natural course of disease progression in patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB), identify potential end points for future therapy trials, and characterize biomarkers related to the disease.A prospective, multicenter study was conducted. Baseline, 6-month, and 12-month assessments included neurodevelopmental status (Bayley Scales of Infant Development, Third edition), adaptive status (Vineland Adaptive Behavior Scales, Second Edition), volumetric brain magnetic resonance imaging, cerebrospinal fluid heparan sulfate, and urine glycosaminoglycan (GAG) measurements.Nineteen patients aged 1.6-31.7 years were enrolled. Over 12 months, cognition, adaptive behavior, and cortical gray matter volume (GMV) declined in most patients. For patients diagnosed at6 years, although there was no overall mean change over 12 months, there were 10%-48%, 3%-66%, and 1%-14% decreases in cognitive development quotient score, Vineland Adaptive Behavior Scales, Second Edition development quotient score, and cortical GMV in 8/12, 9/11, and 10/11 patients, respectively. Mean urine GAG and cerebrospinal fluid heparan sulfate levels were stable, but patients diagnosed at6 years (n = 14) had higher levels than those ≥6 years at diagnosis (n = 4), which was likely associated with age as they also were generally younger.Cognition, adaptive behavior, and cortical GMV measures sensitively tracked deterioration in patients with mucopolysaccharidosis type IIIB aged ≤8.6 years. Biomarkers may have prognostic value, but their sensitivity to disease progression requires further investigation. These findings should help evaluate enzyme replacement and gene therapy agents for this rare, devastating, neurodegenerative disease.ClinicalTrials.gov: NCT01509768.

OBJECTIVE Our objective was to compare a newly designed instrument, the Cone Biopsy Excisor (CBE; Apple Medical Corporation, Bolton, MA), with the standard loop electrosurgical excision procedure (LEEP) for providing a cervical conization specimen with the best achievable margin quality for histological evaluation. METHODS Patients referred to the dysplasia clinics at Hartford Hospital, St. Francis/Mt. Sinai Hospital and the University of Connecticut Health Center/New Britain General Hospital were randomized to either the CBE procedure or LEEP. To be included in the study, patients had to meet at least one of the following criteria: biopsy-proven cervical intraepithelial neoplasia grade 2 or 3, unsatisfactory colposcopy, positive endocervical curettage, or one or more degrees of cytohistological discrepancy. Exclusion criteria included pregnancy, undiagnosed uterine bleeding, acute cervicitis, or biopsy-proven invasive carcinoma. Forty-seven patients were randomized to the CBE and 48 to LEEP. To obtain the cervical specimen, third- and fourth-year obstetricalgynecological residents used Force II Valley Lab Generators (Valley Lab, Boulder, CO) at a blend one setting (80/20 blend of cutting and coagulation). Wattage ranged from 25 to 45, according to the size of the instrument used. Pathological reports were reviewed by the author to determine the amount of fragmentation and for tissue diagnosis. Slides of the specimens were evaluated by two blinded gynecological pathologists. The slides were analyzed for margin quality and thermal damage. A thermal damage score was assigned, evaluating the number of cells affected and the depth of damage. This scoring system, designed by the pathologists, ranged from 3 (least thermal damage) to 9 (greatest thermal damage). RESULTS Of 47 CBE cases and 48 LEEP cases, 41 (87%) and 8 (17%), were single specimens X (1) = 44.6; (p < .0001). The mean number of specimens submitted to pathology per case was 1.2 (+/- 0.6) in the CBE group and 2.3 (+/- 0.9) in the LEEP group (t - 6.89;p < .001). Margins obliterated by thermal artifact included 3 of 47 (6%) in the CBE group and 16 of 48 (33%) in the LEEP group (X (1) = 9.16;p < .003). Mean thermal damage score was 4.1 (± 0.9) in the CBE group and 6.1 (± 1.8) in the LEEP group (t = 6.77; p < .001). CONCLUSION The Cone Biopsy Excisor provides a cervical specimen that exhibits less fragmentation and less thermal damage and has margins that are less likely to be indeterminate than that provided by standard LEEP.