The annual international Lysosomal Storage Diseases conference WORLDSymposium was held in San Diego and online in February 2022. Our Head of Research, Lisa Melton, attended the conference online, and has provided a summary of the key updates on clinical trials for Sanfilippo syndrome that were presented at the conference. It was also very encouraging to see all the other promising research presented at the conference including methods to better measure cognitive outcomes in trials, methods to prevent the immune response to gene therapy so that more children can be treated, and new therapies in development for Sanfilippo types A, B, C and D. If you have any questions, please do get in touch with us.
Transpher A trial (Abeona, ABO-102) for children with Sanfilippo type A
Dr Kevin Flanigan from the Nationwide Children’s Hospital in Ohio, USA, provided an update on the interim results from the trial so far. 22 children aged between 0 to 2 years with rapidly progressing Sanfilippo type A, have been treated with a single intravenous infusion of gene therapy.
No serious safety concerns have emerged in the trial and the data for these children shows that those who were treated at the youngest ages are showing a relatively normal cognitive development trajectory. All the children are also showing a sustained and significant reduction of heparan sulfate in the cerebrospinal fluid (CSF), blood and urine. Secondary storage molecules known as GM2 and GM3 are also reduced. Liver volumes were normalised and preliminary data from measurements of brain volume in MRI scans show that the total brain volume is increasing. This is in contrast to the brain shrinkage seen in untreated children.
It was originally intended that the patients would be followed for 2 years after treatment before data would be presented to the USA Food and Drug Administration for drug approval. However, since the conference, Abeona has announced that the FDA has requested that the children in the study should now be followed until they reach age 5. Unfortunately, this has prompted Abeona to seek a partner to take over the continued development of this drug. We are seeking further information on the implications of this for the Sanfilippo community and will update you as soon as we can.
Autologous Stem Cell Gene Therapy for Sanfilippo type A
Professor Brian Bigger from Manchester University presented an update on this Phase I/II clinical trial. In this trial, patients’ bone marrow stem cells are collected from their blood, treated with gene therapy in the laboratory and then reinfused into the patient where they engraft back into the body.
Five patients aged under two with severe Sanfilippo type A have been treated so far. They will be followed for 3 years and their neurocognitive development compared against the expected development of untreated patients. One additional patient was treated at 30 months of age prior to the trial commencing.
The results show that the treated cells engraft successfully and produce high levels of enzyme. The adverse events experienced by patients are those that are typically associated with bone marrow transplant.
Heparan sulfate reductions of 80-90% were rapidly seen in blood and urine. Reductions in biomarkers in the brain (cerebrospinal fluid) were more delayed, which is due to the time it takes for the transfused cells to populate the brain.
Dr Bigger was unable to present the neurocognitive data for the five youngest patients yet, however, the patient who was treated at 30 months of age has shown a stabilisation of cognitive skills. Professor Bigger concluded by saying that the treatment is well tolerated and that biomarker changes suggest the potential for good clinical outcomes for patients who are treated early.
AAVance gene therapy in children with Sanfilippo type A (Lysogene)
Dr Ralph Laufer from Lysogene presented an update on the phase II/III trial of the AAV-based gene therapy for Sanfilippo type A. In this trial, the gene therapy is injected directly into the brain. 19 patients aged between 10 and 65 months have been treated.
Some abnormalities in the white matter of the brain were observed following treatment which prompted the FDA to place the trial on hold in 2020. However, no clinical symptoms were associated with this and the white matter changes have now been shown to stabilise or decrease after 12 months in all patients. One patient in the trial also died at age 5. Death at this age is rare in children with Sanfilippo, but the treatment was not implicated in the death.
Biomarker data has shown that heparan sulfate levels are decreased by around 23% in the brain. Dr Laufer explained that this partial lowering of heparan sulfate in the brain is expected as gene therapy delivered directly to the brain may not correct enzyme function in the rest of the body, allowing some HS to still flow in from the blood.
Dr Laufer also presented new data on the levels of a protein called neurofilament light (NfL) in the blood. This protein is only released from damaged neurons and has been used in studies of other neurodegenerative diseases and brain injury as a marker of ongoing brain damage.
NfL levels in serum in the Sanfilippo patients treated in this trial were two times lower after treatment than before treatment. This may indicate a positive response to the gene therapy. Longer follow up of the trial participants is needed before cognitive data can be presented.