Tralesinidase Alfa ERT Found to Benefit Sanfilippo Type B Children

Allievex therapy candidate led to clinical gains in Phase 1/2 trial

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An experimental enzyme replacement therapy (ERT) called tralesinidase alfa (AX 250) was found in a clinical trial to safely reduce liver size, slow brain shrinkage, and demonstrate the ability to stabilize cognitive function among children with Sanfilippo syndrome type B.

Tralesinidase alfa also successfully lowered the accumulation of heparan sulfate (HS), a key biomarker of the disease.

“In light of the poor and eventually fatal prognosis and the absence of disease-modifying therapies, tralesinidase alfa has a potential to change the course of the disease in children with [Sanfilippo type B],” the researchers wrote.

The study, “A phase 1/2 study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B,” was published in The Journal of Clinical Investigation.

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Investigating tralesinidase alfa for Sanfilippo type B

As with other forms of Sanfilippo syndrome, type B is marked by the accumulation of heparan sulfate — produced by all cell types and known as HS — inside cells.

In this form of the disease, the buildup is caused by genetic mutations that result in deficient production of alfa-N-acetyl-glucosaminidase (NAGLU), an enzyme involved in breaking down HS.

Patients with this rare type of childhood dementia experience symptoms including brain shrinkage, cognitive and behavioral problems, and enlargement of certain organs including the liver.

Originally developed by BioMarin Pharmaceutical and now owned by Allievex, tralesinidase alfa aims to provide a lab-made version of NAGLU to patients. The enzyme is fused to a protein fragment called insulin-like growth factor-2, which is supposed to help the enzyme be taken up by the right cellular compartments.

Tralesinidase alfa is delivered directly into the cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord. This is done via an intracerebroventricular (ICV) injection — an injection directly into the four CSF-filled cavities in the brain — through a device implanted in the skull.

Preclinical studies have shown that the treatment can increase NAGLU activity and normalize HS levels, thereby reducing disease-associated markers in brain tissue.

The Phase 1/2 open-label trial (NCT02754076), called BMN 250-201, enrolled 22 children, ages 2–9, with Sanfilippo type B. Among the participants were 13 boys and nine girls.

Part 1 of the trial was a dose escalation study, in which three children received increasing doses of the therapy — 30, 100 and 300 mg — once per week for up to 28 weeks, or about six months. Results showed that 300 mg was the maximally tolerated dose.

In Part 2, these three patients, along with 19 others recruited from a previous observational study (NCT02493998) of Sanfilippo type B’s natural history, were given tralesinidase alfa (300 mg) once per week for 48 weeks, or almost a year.

Previously presented interim results showed that the treatment was well-tolerated, restored HS levels, reduced liver size — which is typically enlarged in the disease — and halted cognitive declines.

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Full trial results are promising for tralesinidase alfa

Researchers now have published full results from the trial, which are generally consistent with those interim findings.

The most common treatment-emergent side effects included vomiting, fever, upper respiratory tract infections, headache, and increased white blood cell counts in the CSF — a condition known as pleocytosis.

Serious adverse events considered related to the treatment were CSF pleocytosis, vomiting, fluctuating consciousness, fever, and angioedema, or swelling under the skin. Serious side effects related to the ICV device included infection, device malfunction, CSF leakage, and wound infection.

According to the researchers, these side effects are “consistent with known complications of enzyme replacement therapy (ERT), i.c.v. devices and/or neurodegenerative disease in pediatric populations.”

One patient dropped out of the study due to a serious adverse event that was not considered related to the experimental treatment.

Results also showed that the treatment was efficiently distributed throughout the brain and was quickly absorbed. This was accompanied by a normalization of HS levels in the CSF and blood within the first weeks of treatment that were sustained for up to a year with the 300 mg dose.

Importantly, reductions in HS were associated with clinical improvements, including a significant reduction in liver and spleen size after a year of treatment for most patients.

In light of the poor and eventually fatal prognosis and the absence of disease-modifying therapies, tralesinidase alfa has a potential to change the course of the disease in children with [Sanfilippo type B].

The treatment also led to stabilizations in the volume of the brain’s cortical gray matter, meaning primarily cells bodies of neurons in the outermost layer of the brain. A stabilization in cognitive function also was observed for some patients — a contrast to the progressive decline usually observed in Sanfilippo B patients.

However, “a treatment duration of longer than 48 weeks will be needed to establish whether there is a clinically meaningful benefit on cognition related to treatment with tralesinidase alfa,” the researchers wrote.

Still, a significant correlation was observed between blood levels of tralesinidase alfa and changes in cognition. The few participants with the highest and most sustained exposure to the medication in the blood saw the most cognitive gains.

While some patients developed antibodies against the treatment, this did not overall affect HS normalization, resolution of liver enlargement, or the rate of cognitive decline.

An open-label extension phase of the trial (NCT03784287), called BMN 250-202, is evaluating the long-term safety and effectiveness of the treatment for up to 4.5 years.

“Other long-term effects on sleep behavior, hearing, and other quality of life measures are being monitored and will be reported in a future publication,” the researchers wrote.

The study was funded by BioMarin and Allievex.