Safety evaluation of chronic intrathecal administration of heparan N-sulfatase in juvenile cynomolgus monkeys

Abstract

An intrathecal (IT) formulation of recombinant human heparan N-sulfatase (HNS) is under development for the treatment of the neurological symptoms of mucopolysaccharidosis IIIA (MPS IIIA; Sanfilippo A disease), the defining clinical feature of this disorder. Since the average age of MPS IIIA patients is 4.5 years, the pivotal toxicology studies for HNS were conducted in juvenile cynomolgus monkeys to evaluate the effects on the developing brain. Monkeys were implanted with an IT-lumbar drug delivery device and dosed every other week by slow bolus administration (1.5, 4.5, or 8.3 mg/dose HNS for 6 months; 12 doses), with device and vehicle controls receiving phosphate-buffered saline or vehicle, respectively. Eight animals per group (four/sex) were necropsied at 3 and 6 months (device control group necropsied at 3 months), and eight animals from the vehicle group and the three HNS-dosed groups were necropsied 1 month after the final IT dose. No HNS-related clinical signs or gross central nervous system lesions were observed. Compared with controls, there were cellular infiltrates of slight-to-minimal mean severity in the meninges/perineurium surrounding the brain/spinal cord correlating with transient increases in cerebrospinal fluid (CSF) leukocytes, predominantly eosinophils, which largely resolved 1 month after the final dose. These changes were not associated with any adverse morphological changes in the brain or spinal cord. There appeared to be a dose-related trend toward higher mean CSF HNS levels and in tissue HNS activity levels in the brain, spinal cord, and liver. The no-observed-adverse-effect-level was 8.3 mg/dose given every other week, the highest dose administered.

Nonclinical comparability studies of recombinant human arylsulfatase A addressing manufacturing process changes

“…The original clinical trial application was supported by a nonclinical program similar to that described by Pfeifer et al . [ 13 ], and in line with good laboratory practice for nonclinical laboratory studies [ 19 ].…”

“…The decrease in LAMP-1 staining observed in the pharmacodynamic comparability study thus serves as a potential indicator of the therapeutic effects of rhASA. Animal studies conducted by other researchers have also yielded safety and activity data for intrathecal drug delivery to the brain, providing further support for this method of administration [ 12 , 13 , 15 , 32 ].…”

Whole Body and CNS Biodistribution of rhHNS in Cynomolgus Monkeys after Intrathecal Lumbar Administration: Treatment Implications for Patients with MPS IIIA

“…Determining the extent of penetration beyond the site of injection, and in particular, the disposition of rhHNS in the cerebrospinal space with respect to the exposure of specific brain structures or cell types to rhHNS, is important in assessments of therapeutic potential or, conversely, the safety risks of treatment. Previous to the present studies, a safety and tolerability experiment with IT rhHNS in juvenile cynomolgus monkeys found a minimal increase in CNS cellular infiltrates which resolved within one month of the last dose and which were not associated with any adverse clinical signs, gross CNS lesions, or morphological changes in the brain or spinal cord [ 4 ]. A trend in dose-to-rhHNS CSF concentration and to rhHNS activity in CNS tissues was also demonstrated.…”

“…Recombinant human heparan N -sulfatase (rhHNS) is an investigatory enzyme replacement therapy (ERT) for the treatment of MPS IIIA. Intravenous (IV) delivery of rhHNS has not demonstrated appreciable CNS penetration needed for therapeutic treatment of the neurocognitive degeneration [ 4 ]. Formulation of rhHNS for intrathecal (IT) administration allows direct delivery to the CNS via the cerebral spinal fluid (CSF).…”

“…Formulation of rhHNS for intrathecal (IT) administration allows direct delivery to the CNS via the cerebral spinal fluid (CSF). Evidence of the tolerability of chronic intrathecal administration of rhHNS was initially provided in a device- and vehicle-controlled safety evaluation in cynomolgus monkeys dosed every two weeks over six months at three dose levels [ 4 ]. In a subsequent open-label, phase 1/2 dose-escalation, safety trial in 12 human patients for a total of six doses, rhHNS administered via an intrathecal drug delivery device (IDDD) was generally well tolerated [ 5 ].…”