Study supports therapy dose used in youth in Sanfilippo type B trial

Aug 09, 2023

Study supports therapy dose used in children in Sanfilippo type B trial

by Lindsey Shapiro, PhD | June 1, 2023

Tralesinidase alfa, an experimental enzyme replacement therapy for people with Sanfilippo syndrome type B, was safe and showed good brain distribution in non-human primates, specifically cynomolgus monkeys, a new study found.

The treatment was equally well tolerated regardless of dose, duration of the infusion, or formulation.

According to the scientists, the findings overall support the dosing regimen used for children with Sanfilippo type B in a recent Phase 1/2 clinical trial (NCT02754076) and its ongoing open-label extension phase (NCT03784287). The pediatric patients involved in that study are being treated with tralesinidase alfa once per week.

In the new research, "juvenile monkeys between 11- and 14-months of age were used, which is a relevant age window, since pediatric patients have been included in clinical trials with [tralesinidase alfa]," the scientists wrote.

The study, "Safety, pharmacokinetics and CNS distribution of tralesinidase alfa administered via intracerebroventricular infusion to juvenile cynomolgus monkeys," was published in Toxicology Reports.

In Sanfilippo type B, a molecule called heparan sulfate builds up to toxic levels inside cells. This occurs as a result of genetic mutations that lead to deficient production of alfa-N-acetyl-glucosaminidase (NAGLU), an enzyme involved in breaking down heparan sulfate.

Nerve cells and other cell types in the brain are particularly susceptible to the toxic effects of heparan sulfate, and thus, patients experience a form of childhood dementia marked by behavioral symptoms and developmental regression.

Also known as AX 250, tralesinidase alfa is an experimental enzyme replacement therapy that provides patients with a lab-made version of NAGLU, made with certain modifications to help it be taken up by the right cellular compartments.

It's given by intracerebroventricular (ICV) infusion — an infusion directly into the fluid-filled cavities in the brain — via a device implanted in the skull. That mode of delivery allows for the therapy to be effectively distributed in the brain.

Originally developed by BioMarin Pharmaceutical, tralesinidase alfa is now owned by Allievex, a Massachusetts-based company. Backed by preclinical studies in cell, mouse, and dog models, the therapy is now being tested in children with Sanfilippo type B.

Now, researchers at BioMarin and Allievex sought to learn more about the safety and brain distribution of tralesinidase alfa when given at various doses and infusion rates in juvenile non-human primates — monkeys.

Across a series of experiments, the researchers found that tralesinidase alfa — at doses of 8, 24, or 73 mg — was well tolerated with no notable safety signals. The therapy was administered as a single ICV infusion or as once weekly infusions over a five-week period.

The researchers noted that the therapy was similarly well tolerated when given as a standard infusion, which is slowly delivered over four hours, or as a five-minute infusion. That shorter infustion, called a bolus, delivers the same amount of medication over a much shorter period of time.

Finally, the researchers examined the effects of two new formulations of the therapy, each utilizing a different vehicle for carrying the medication into the body. Both were well tolerated.

The ICV infusion was associated with increases in white blood cell counts in the cerebrospinal fluid (CSF) — the fluid that fills the cavities where tralesinidase alfa is infused. Those cells increased with increasing tralesinidase alfa doses, but also were seen in animals given a placebo (vehicle only).

Some brain lesions were observed along the area where the tube (catheter) that delivers the ICV infusion was placed. Other cellular changes also were associated with the catheter placement. These included immune cell infiltration, inflammation, scarring, tissue death, and clotted blood.

None of the alterations were specific to tralesinidase alfa itself, however. Instead, all of these catheter-related changes are "expected consequences of the use of [human] devices in nonclinical species," the scientists wrote.

Across all doses, formulations, and modes of delivery, the therapy was well distributed in the brain after ICV administration. The data support "weekly or every-other-week dosing in the clinic," according to the researchers.

We have demonstrated the safety, tolerability and favorable … distribution of [tralesinidase alfa] after single or multiple ICV administrations via a slow or fast infusion to juvenile non-human primates.

Antibodies against the therapy were observed in some animals but did not influence the brain's overall exposure to the treatment, consistent with previous findings that such antibodies did not influence the therapy's effectiveness.

After ICV administration, low levels of tralesinidase alfa reached the bloodstream, which researchers believe occurred via drainage through the lymphatic system, the brain's waste clearance mechanism.

"We have demonstrated the safety, tolerability and favorable … distribution of [tralesinidase alfa] after single or multiple ICV administrations via a slow or fast infusion to juvenile non-human primates," the researchers wrote.

Overall, according to the team, the safety findings in non-human primates were similar to previous studies in dogs and data from children with Sanfilippo in the Phase 1/2 clinical trial.

Data from that trial also found that tralesinidase alfa reduced liver size, slowed brain shrinkage, and stabilized cognitive function in patients.