SOBI003 Safe, Reduces Heparan Sulfate Levels in 1st Trial in Humans

Experimental Sanfilippo treatment's development stopped for business reasons

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with SOBI003, a now-discontinued experimental therapy for Sanfilippo syndrome type A, was generally well-tolerated and reduced heparan sulfate levels in a clinical trial.

“These are very important findings that could inform future trials and therapeutic development programs targeted at reduction of heparan sulfate. They also provide important information in considering the use of [heparan sulfate] as a surrogate biomarker in Sanfilippo syndrome,” Cara O’Neill, chief science officer at the Cure Sanfilippo Foundation, said in a press release.

The study, “Chemically modified recombinant human sulfamidase (SOBI003) in mucopolysaccharidosis IIIA patients: Results from an open, non-controlled, multicenter study,” was published in Molecular Genetics and Metabolism. The work was funded by Swedish Orphan Biovitrum AB (Sobi).

Sanfilippo syndrome type A is caused by mutations in the gene that provides instructions for making an enzyme called sulfamidase, which is needed to break down a molecule called heparan sulfate (HS). Consequently, HS builds up to toxic levels, ultimately causing disease symptoms.

SOBI003 is a version of the sulfamidase enzyme that is modified to permit better entry into the brain. Sobi was developing the therapy, but the company announced in 2021 that it was discontinuing development. This decision was made based on business strategy, unrelated to data about the therapy’s efficacy or safety.

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Sanfilippo Type B Progression Has Similar Trajectory to Type A: Study

Trial data now published

Sobi sponsored a first-in-human Phase 1/2 clinical trial (NCT03423186) that began in 2018 to test SOBI003 in children with Sanfilippo type A. Here, scientists at Sobi and other institutions published data from the completed study.

The trial enrolled six children with Sanfilippo A at two sites in the U.S. and one in Turkey. Half of the patients were treated with SOBI003 at a dose of 3 mg/kg, while the other half were dosed at 10 mg/kg, given as a weekly infusion for 24 weeks (about half a year). An antihistamine was given before each infusion.

The trial was originally planned to include a third group of patients given a higher dose, but Sobi terminated development of the therapy before that group was started.

Among the six patients in the trial, two were female and four were male, and the age at initiation of treatment ranged from 15 months (just over one year) to 65 months (about 5.3 years).

All six participants completed the initial trial and enrolled in an open-label extension (NCT03811028), where they continued to be treated with SOBI003 for up to 104 weeks (about two years). During this period, dosage of SOBI003 could be adjusted at the discretion of the treating investigator, up to a maximum dose of 20 mg/kg. Five of six patients were on this max dose at the latest assessment.

Most side effects of treatment were judged mild or moderate in intensity, with the most common effects being skin or heart abnormalities. One patient in the low-dose group reported a cluster of severe side effects, including rash, slowed heart rate, swelling, and vomiting, which all occurred on the same day.

All but one of the patients experienced multiple infusion-related reactions (IRRs), with common symptoms including hives, decreased heart rate, decreased oxygen levels in blood, and vomiting.

“Weekly infusions of SOBI003 at doses of 3 mg/kg, 10 mg/kg and 20 mg/kg were considered to be generally well tolerated,” the researchers concluded.

Antibodies against the SOBI003 therapy were found in samples of blood from all patients shortly after starting the therapy. Anti-drug antibodies (ADAs) also were found in cerebrospinal fluid (CSF), the liquid that surround the brain and spinal cord. One patient with comparatively low levels of these antibodies experienced no IRRs.

Overall, the available data “strongly suggest that ADA titers [levels] impacted on [the pharmacological properties] of SOBI003, and possibly also on the incidence of IRRs,” the researchers wrote.

Upon entering the study, all six children had abnormally high levels of HS in their blood, urine, and CSF, which was expected given that they had Sanfilippo A. Analyses showed a marked drop in HS levels during treatment with SOBI003, with most patients showing near-normal HS levels in blood and urine. At the last trial assessment, the average HS decrease in CSF was 79%. The reduction in HS showed a clear correlation with SOBI003 dose.

In neurocognitive assessments, two patients showed an improvement with SOBI003 treatment, while the other four showed stable or only slightly declining measures. A standardized assessment of adaptive behavior showed generally stable scores over time.

“While no clear overall effect could be shown on neurocognitive development … AEq [adaptive behavior age-equivalent] showed a stabilization of cognition for all patients,” the team wrote. Assessments of life quality and sleep patterns “did not reveal any treatment-induced trends,” they noted.

“Given the unmet medical need of these patients, one may have wished for a clearer efficacy signal; however, this phase 1/2 study was neither designed nor powered to demonstrate a clinical effect,” the researchers wrote, stressing that this first-in-human study was mainly designed to assess safety.

“We THANK the families that participated in the Sobi trial and share with them the heartbreak that likely continues since the discontinuation of this clinical trial program and potential therapy,” O’Neill said. “We continue to work hard to make more opportunities to participate in clinical trials available for children.”