BioMarin Presents Phase 1/2 Interim Results for Enzyme Replacement Therapy in Sanfilippo B Syndrome

BioMarin Pharmaceutical announced interim results for its Phase 1/2 trial evaluating BMN 250, an enzyme replacement therapy, for the treatment of Sanfilippo B syndrome, also called mucopolysaccharidosis IIIB.

The results, presented at WORLDSymposium 2018, show that treatment with BMN 250 via brain infusions helped restore normal levels of heparan sulfate, an important biomarker of the disease, in the central nervous system, and it reduced the size of patients’ livers.

Importantly, cognitive impairment in patients treated with BMN 250 also stabilized, according to the study’s interim results.

BMN 250 is composed of a human NAGLU enzyme, together with a small protein derived from insulin-like growth factor 2 (IGF2). It is administered via intracerebroventricular infusions, through a reservoir and catheter connected to the patient’s brain. This particular method of administration bypasses the blood-brain barrier and other mechanisms that limit a therapy’s distribution in the brain.

The Phase 1/2 clinical trial (NCT02754076) primarily evaluates the safety, tolerability, and effects of BMN 250 on the cognitive function of patients with Sanfilippo B. Secondary outcome measures include studying immunogenicity, or immune response, and the maximum concentration of BMN 250 in cerebrospinal fluid (CSF) and plasma. Additionally, researchers also are studying glycosaminoglycan (GAG) levels in CSF, plasma, and urine, and the impact of BMN 250 treatment on brain structure, as assessed by magnetic resonance imaging (MRI).

In the completed dose escalation part of the study (part 1), three patients received escalating doses of BMN 250 (30 mg, 100 mg, and 300 mg) for up to 12 months to test the therapy’s safety and activity.

In the second phase, patients will receive 300 mg weekly doses of the compound over 48 weeks while their cognitive function is assessed.

High levels of heparan sulfate in cerebrospinal fluid — body fluid that circulates in the spinal cord and the brain — are an important biomarker of Sanfilippo B syndrome. This occurs because patients with Sanfilippo B syndrome cannot produce, or produce less of, one of the enzymes necessary for heparan sulfate degradation.

In six patients treated with BMN 250, the levels of heparan sulfate in cerebrospinal fluid rapidly dropped to normal. Data from three BMN 250-treated patients also showed a decrease in liver size, which is typically enlarged in patients with the condition.

In untreated patients, the developmental quotient — a measure of cognitive function normalized to age — tends to progressively decline. However, in three patients treated with BMN 250, the development quotient stabilized, suggesting that the compound was able to stop the debilitation of cognitive capacity.

The interim safety data indicate that BMN 25o is well-tolerated by patients. The most common adverse effects associated with the compound were fever, an increase in cell number in cerebrospinal fluid, vomiting, and headache.

“These studies are generating a robust data set to determine the safety and efficacy of BMN 250 in Sanfilippo B,” Hank Fuchs, MD, president of worldwide research and development at BioMarin, said in a press release.

“While it is still very early, we are encouraged that the interim data is showing normalization of an important biomarker and liver size, as well as suggesting a stabilization in cognitive decline. We appreciate the support of the Sanfilippo community to study this experimental treatment, and we remain committed to contributing to the body of scientific knowledge of this devastating disease,” he added.

In addition to this clinical trial, BioMarin is conducting two other studies in Sanfilippo B syndrome patients: an observational study of the progression of Sanfilippo B over time in children 1-10 years of age (NCT02493998), and a natural history study of the progression of Sanfilippo B over time in children and teenagers up to 18 years of age (NCT03227042).