SOBI003, Swedish Orphan Biovitrum AB (Sobi)’s chemically modified version of sulfamidase — the missing enzyme in Sanfilippo syndrome type A — is superior to its original version at reaching and persisting in the brain, a study in rats suggests.
The study, “Impact of chemical modification of sulfamidase on distribution to brain interstitial fluid and to CSF after an intravenous administration in awake, freely-moving rats,” was published in the journal Molecular Genetics and Metabolism Reports.
Sanfilippo syndrome type A, also known as mucopolysaccharidosis type IIIA (MPSIIIA), is a rare disease caused by a deficiency in the sulfamidase enzyme. This deficiency leads to the toxic accumulation of heparan sulfate and other long-sugar molecules inside cells, causing progressive damage.
The central nervous system (CNS) — the brain and spinal cord — is the most severely affected system in those with Sanfilippo type A. One of the main physiological obstacles in the development of therapies for this disease is finding a treatment that can penetrate the blood-brain barrier, the protective membrane that prevents some molecules in the blood from reaching the brain.
Intravenous delivery — directly into the bloodstream — of a healthy version of sulfamidase as an ERT was ineffective in treating brain damage in a mouse model of Sanfilippo type A. However, its delivery into the cerebrospinal fluid (CSF), which is the liquid surrounding the brain and spinal cord, showed promising results.
Still, a Phase 2b trial (NCT02060526) — which showed that administration of sulfamidase into the CSF reduced heparan sulfate levels in the cerebrospinal fluid of infants with early-stage Sanfilippo type A — failed to prevent neurocognitive decline.
Sobi has now developed a chemically modified version of sulfamidase, called SOBI003, that has the potential to be superior as an ERT for Sanfilippo type A. While maintaining the enzyme’s structure and function, the induced modification strongly reduces its uptake into non-CNS tissues, extending its presence in the body and potentially improving its ability to reach the CNS.
Preclinical studies have shown that intravenous delivery of SOBI003 can reduce the levels of heparan sulfate and other disease biomarkers in the brain in a mouse model of Sanfilippo type A.
These positive data supported the initiation of a Phase1/2 clinical trial, called SOBI003-001 (NCT03423186), evaluating the safety and effectiveness of SOBI003 delivered intravenously for 24 weeks. The study includes up to nine children with Sanfilippo type A, who have not received prior treatment.
SOBI003-001 is still recruiting patients, ages 1 to 6, in the U.S., Germany, and Turkey. More information on enrollment contacts and locations can be found here. After completing the study, participants may choose to enter an extension study (NCT03811028), in which they will continue treatment for up to 80 weeks (around one and a half years).
Now, Sobi’s researchers, in collaboration with a scientist in the Netherlands, investigated the impact of chemically modifying sulfamidase on the enzyme’s pharmacokinetics — its uptake, distribution, and elimination in the body.
The team analyzed the levels of either the modified (SOBI003) or the original version of sulfamidase in the blood, CSF, and brain fluid of awake, freely moving rats over four days after a single intravenous administration.
The results showed that the levels of both sulfamidase versions were always higher in the blood than in the CSF or brain, supporting the notion that these versions have “a low passage across the blood-CSF and blood brain barriers,” the researchers said.
While blood levels of both versions were similar right after therapy administration, SOBI003 showed sustained higher levels later on when compared with the original enzyme. This resulted in an overall exposure to SOBI003 that was 18-fold higher in the blood, seven-fold higher in the CSF, and 48-fold higher in the brain, than that of the original version.
SOBI003 concentrations in the blood also showed a more gradual decline when compared with those from the original enzyme.
Notably, SOBI003 brain levels were slightly higher than those of the original enzyme right after treatment administration and achieved a higher peak a few hours later, indicating that SOBI003 was more efficient in reaching the brain.
These data suggested that there was an association between the blood levels of the enzyme and its levels in the CSF and brain, and that the chemical modification of sulfamidase increased brain exposure to the enzyme.
However, future studies are necessary to better understand “the impact of chemical modification on the ability of [SOBI003] to reach various target cells in the brain,” the researchers said.
SOBI003 has received orphan drug designation from both the European Medicines Agency and the U.S. Food and Drug Administration (FDA) for Sanfilippo syndrome type A, and fast track status from the FDA. These designations are expected to accelerate the therapy’s clinical development and regulatory review.