Allievex’s enzyme replacement therapy, called tralesinidase alfa or AX 250, is delivered via weekly injection into the fluid that bathes the brain and spinal cord (the cerebrospinal fluid, or CSF) via a drug delivery device and a port implanted under the scalp. Tralesinidase alfa features the NAGLU enzyme fused to another protein called insulin-like growth factor-2 (IGF-II), which helps NAGLU enter cells and the lysosome.
The study was conducted in two parts. In Part 1, three patients received increasing doses of the ERT - starting at 30 mg of enzyme per week, moving to 100 mg, and finally 300 mg per week. Part 2 of the study included these three patients and 19 others who received the ERT at 300 mg per week for 48 weeks. Age eligibility for the study ranged from 1-11 years. Of the 22 patients in Part 2, nine were female, 13 were male, and the average age at the first dose was 60 months.
Adverse events seen during the study were most likely related to the ERT itself and included vomiting, fever, and increased numbers of immune cells in the CSF. Serious adverse events were also noted due to the drug delivery device, which included infections, CSF leakage, and device malfunction. However, the investigators note that these side effects are expected when using this drug delivery device for ERT.
Most patients developed antibodies to the ERT that were detected in the blood or the CSF, though the levels appeared to stabilise by week 36. While this indicates their immune systems were reacting to the ERT, experiments using cells in the lab suggest the antibody levels would not have been high enough to neutralise the therapy.
In Part 1 of the study, heparan sulphate levels were reduced by all three doses, but only the 300 mg dose was sufficient to normalise the levels in both the blood and CSF. In 20 of the 22 patients in Part 2 of the trial total heparan sulfate also reduced to, and remained at, normal levels over the 48-week period.
Overall, there was a significant reduction in the liver and spleen sizes in patients at 48 weeks compared to the start of the study.
To see the effect on brain volume, investigators measured the volume of the grey matter in the cortex - the outer layer of the brain, which often starts to shrink in patients with Sanfilippo type B in their first decade of life. At the start of the study, patients in Part 2 had an average volume of 471 mL compared to the volume of unaffected children of 489 mL. Investigators found an average of 58 mL of volume was lost in the first 24 weeks but only 2 mL on average in the second 24 weeks. They note that this early loss of brain volume may reflect clearance of heparan sulfate, and possibly also reduction in inflammation as a result of the treatment. Only two patients did not lose grey matter volume in the cortex, which included the youngest patient in the study.
The cerebellum is a part of the brain below the cortex that is involved in tasks like movement and coordination. When looking at the average volume of the cerebellum, it appeared this part of the brain also appeared to grow in the 48 weeks of the study.
Overall, the data show that AX 250 can alter the natural course of the disease with respect to features like heparan sulfate levels, liver size, and cortical grey matter volume. Additional data will be needed to confirm if the potential therapy can halt or slow cognitive decline in patients.
Most patients are continuing to receive enzyme and will be monitored in a follow-up study for 240 weeks, and a further extension study for an additional 144 weeks to determine the long-term effects of AX 250 on neurocognition.
The trial was initially sponsored by BioMarin Pharmaceutical before it was licensed by Allievex Corporation in October 2019.
More information on therapy avenues for Sanfilippo can be found on our website: https://www.sanfilippo.org.au/research/therapy-avenues