safety, tolerability, ascending dose and dose frequency study of rhhns via an iddd in mps iiia patients

Conditions: Mucopolysaccharidosis (MPS)

Summary: sanfilippo syndrome, or mucopolysaccharidosis (mps) iii, is a rare lysosomal storage disease (lsd) caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan (gag) heparan sulfate (hs) in lysosomes. mps iiia results from deficiency of the enzyme heparan n-sulfatase (sulfamidase). mps iiia symptoms arise on average at 7 months of age, with the average age of diagnosis at 4.5 years for the majority of patients. the central nervous system (cns) is the most severely affected organ system in patients with mps iiia, evidenced by deficits in language development, motor skills, and intellectual development. in addition, there are abnormal behaviors including but not limited to aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.overall, individuals with mps iiia have a marked developmental delay and significantly reduced lifespan of 15 years of age on average. the purpose of this study is to determine the safety and tolerability of rhhns via ascending doses administered via an a surgically implanted intrathecal drug delivery device (iddd) intrathecal (it) route once monthly (or every two weeks) for 6 months in patients with mps iiia.

no effective, disease-modifying therapies are currently approved as treatments for this devastating and disabling disease. shire human genetic therapies (shire hgt) is developing a sulfamidase enzyme replacement therapy (ert)rhhns for patients with mps iiia. recombinant human heparan-n-sulfatase (rhhns) is being administered into the cerebrospinal fluid (csf) via an surgically implanted intrathecal drug delivery device (iddd), because when administered intravenously (iv) it does not cross the blood brain barrier (bbb). this study is a multicenter, multiple-dose, dose escalation study designed to evaluate the safety, tolerability, and clinical activity of up to 3 dose levels (10mg,45mg and 90mg monthly for 6 months) of rhhns administered via an iddd in patients with sanfilippo syndrome type a ages greater than or equal to 3 years of age. patients who have completed all study requirements in this study will be invited to participate in an open-label extension study that will be designed to evaluate long term safety and clinical outcomes of intrathecal administration of rhhns.

Eligibility criteria:
inclusion criteria each patient had to meet the following criteria to be eligible for the study: 1. a.) patients had a documented deficiency in sulfamidase enzyme activity of ≤10% of the lower limit of the normal range as measured in fibroblasts or leukocytes. and either b or c b.) patients had a normal enzyme activity level of at least 1 other sulfatase (to rule out multiple sulfatase deficiency) as measured in fibroblasts or leukocytes. c.) patients had 2 documented mutations. 2. the patient was ≥3 years of age and had a developmental age ≥1 year. 3. patients must have been medically stable, in the opinion of the investigator, to accommodate the protocol requirements, including travel, assessments, and iddd surgery, without placing an undue burden on the patient/patient's family. 4. the patient's parent(s) or legal guardian must have voluntarily signed an institutional review board/independent ethics committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient, the patient's parent(s), or legal guardian. the patients, patient's parents or legal guardian's consent and patient's assent as appropriate, must have been obtained. exclusion criteria patients who met any of the following criteria were excluded from the study: 1. the patient had significant non-mps iiia related cns impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments, as determined by the investigator. 2. the patient had mps iiia behavioral-related issues, as determined by the investigator, that would have precluded performance of study neurocognitive and developmental testing procedures 3. the patient was pregnant, breast feeding, or was a female patient of childbearing potential who would not or could not comply with the use of an acceptable method of birth control such as condoms, barrier method, oral contraception, etc. 4. the patient was blind and/or deaf. 5. the patient had any known or suspected hypersensitivity to anesthesia or was thought to have an unacceptably high risk for anesthesia due to airway compromise or other conditions. 6. the patient or the patient's family had a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns. 7. the investigator may have chosen to exclude patients who have had complications resulting from prior lumbar punctures. 8. the patient had a cns shunt. 9. the patient had skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the iddd. 10. the patient had a history of poorly controlled seizure disorder. 11. the patient was currently receiving psychotropic or other medications, which in the investigator's opinion, would have been likely to substantially confound test results and the dose and regimen of which cannot be kept constant throughout the study. 12. the patient could not sustain absence from aspirin, non-steroidal medications, or medications that affected blood clotting within 1 week prior to a relevant study related procedure (eg, device implantation if applicable), or had ingested such medications within 1 week before any procedures in which any change in clotting activity would have been deleterious. 13. the patient had received treatment with any investigational drug or a device intended as a treatment for mps iiia within the 30 days prior to, or during the study, or was enrolled in another study that involved an investigational drug or device (screening through safety follow-up contact). 14. the patient received a hematopoietic stem cell or bone marrow transplant. 15. the patient's parent(s), or patient's legal guardian(s) was/were unable to provide consent or the patient could not provide assent, as appropriate, due to, but not limited to, the inability to understand the nature, scope, and possible consequences of the study, or did not agree to comply with the protocol defined schedule of assessments.

Keywords: mucopolysaccharidosis (mps) iiia recombinant human heparan n-sulfatase (rhhns) sanfilippo syndrome type a (mps iiia) lysosomal storage disease (lsd) intrathecal drug delivery device (iddd)