Tralesinidase Alfa Shows Promise in Dog Model of Sanfilippo B
ERT candidate found to improve cognition and reduce brain shrinkage
Tralesinidase alfa (AX 250), an experimental enzyme replacement therapy for Sanfilippo syndrome type B that’s now in clinical trials, was found to improve cognition and reduce brain shrinkage in a dog model of the disease, a new study reports.
“The data presented here support the current human clinical dose of [tralesinidase alfa] for the treatment of [Sanfilippo B] disease,” the researchers wrote.
Moreover, “these findings demonstrate the ability of [tralesinidase alfa] to prevent or limit the biochemical, pathologic [disease-causing], and cognitive manifestations of canine [Sanfilippo type B] disease, thus providing support of its potential long-term tolerability and efficacy in [human patients],” the team wrote.
The study, “Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB,” was published in The Journal of Pharmacology and Experimental Therapeutics.
The work was funded by Allievex, the company developing tralesinidase alfa. It also was supported by the therapy’s original developer, BioMarin Pharmaceutical.
In Sanfilippo type B, genetic mutations result in low or no production of alpha-N-acetylglucosaminidase, known as NAGLU, an enzyme needed to break down a complex sugar molecule called heparan sulfate, or HS.
As a result, HS builds up to toxic levels in cells, especially nerve cells, ultimately leading to disease symptoms like cognitive and behavioral difficulties, as well as an enlarged liver.
Testing tralesinidase alfa in humans
Enzyme replacement therapy (ERT) for Sanfilippo type B aims to deliver a working version of the NAGLU enzyme to patients, allowing proper clearance of HS.
Tralesinidase alfa is an experimental ERT that consists of a lab-made NAGLU enzyme attached to a piece of another protein — called insulin-like growth factor 2 — that’s designed to help it get into cells.
The therapy is injected directly into the cerebrospinal fluid (CSF), which is the liquid surrounding the brain and spinal cord. It is administered into the cerebral ventricles, the four fluid-filled interconnected cavities in the brain.
This mode of administration bypasses the blood-brain barrier, a highly selective membrane that prevents large molecules in the blood from reaching the brain. While this membrane works to protect the brain from foreign invaders, it’s often a key obstacle for brain-targeting therapies in fighting disease.
Previous studies in animal models of Sanfilippo, and in lab-grown cells from patients, showed that tralesinidase alfa was able to increase NAGLU activity. It also normalized HS levels and reversed several disease-specific tissue changes.
The therapy was granted orphan drug status in both the U.S. and Europe. That designation is meant to accelerate a medication’s clinical development and regulatory review.
In a Allievex-sponsored Phase 1/2 trial (NCT02754076), treatment with tralesinidase alfa was shown to stabilize cognitive function and reduce HS levels. That study, completed in 2020, enrolled 23 children, ages 1–10, with Sanfilippo B.
An ongoing extension study (NCT03784287) is evaluating the long-term safety and effectiveness of 300 mg of tralesinidase alfa, given weekly over 4.5 years, in 20 of the children.
Now, researchers reported the long-term effects of tralesinidase alfa in a dog model of Sanfilippo B.
“Larger animal model of [Sanfilippo] have been critical to the advancement of therapies and are well suited to preclinical confirmation of the safety, efficacy, and pharmacologic activity of potential therapeutics,” the scientists wrote.
The therapy was administered at a dose of either 12 or 48 mg every other week for up to 20 months, The 48 mg dose, corresponding to about 480 mg weekly in pediatric patients, “was selected because it is the maximum feasible dose, and it provides a sufficient safety margin over the clinical dose (300 mg weekly),” the team wrote.
Dogs in this model normally show a pronounced accumulation of HS in the central nervous system (CNS), comprised of the brain and spinal cord, as well as in other bodily tissues.
Results in the dog model
Tralesinidase alfa treatment resulted in a “statistically significant, dose-dependent reduction of HS and HS-NRE levels in both CSF and CNS tissue” of these animals, the researchers wrote.
HS-NRE, or HS with N-acetylglucosamine terminating nonreducing ends, is the specific form of the molecule that is targeted by the NAGLU enzyme.
In dogs treated with the higher dose, HS and HS-NRE levels in CSF and CNS tissue were reduced to near-normal levels within weeks of treatment.
These findings suggest “widespread distribution and uptake” of the therapy, even though antibodies against the medication were eventually detected in the CSF of all dogs, the researchers wrote.
Notably, HS and HS-NRE levels in the CSF mirrored those in the CNS, supporting their use “as surrogates for treatment effects on the levels in CNS tissue since brain tissue cannot be biopsied in the clinic,” the team wrote.
Analyses of the dogs’ brains found that those treated with tralesinidase alfa showed less pronounced structural changes, less shrinkage, and reduced inflammation. The treatment also decreased markers of dysfunction of the lysosome — the cellular compartment that houses the NAGLU enzyme.
In untreated dogs with Sanfilippo B-like disease, researchers discovered progressive deficits on laboratory tests of learning and memory. These deficits mirrored the cognitive difficulties seen in humans with the disorder. Treatment with tralesinidase alfa led to statistically significant improvements in these scores.
“Together with the improved neuroimmune response and lysosomal storage burden in [several brain regions], these data suggest that less brain [shrinkage] and disease [features] correspond to a better cognitive outcome in [Sanfilippo B] dogs,” the researchers wrote.
While the ERT was given directly into the brain, the researchers noted that its administration also was associated with reduced liver enlargement. That suggests that this type of administration can also have benefits elsewhere in the body.
These findings suggest that sustained normalization of HS and HS-NRE in the CSF “could be an appropriate surrogate endpoint reasonably likely to predict clinical benefit in humans,” the team wrote.
Also, tralesinidase alfa was generally well-tolerated, without any overt signs of toxicity in the animals.
The researchers concluded that the data support the medication dose being used in the ongoing clinical trial in Sanfilippo B patients.