Sanfilippo Awareness Day: A Peek Into the CGT Pipeline


CGTLive takes a look at MPSIII therapies in the pipeline for World Sanfilippo Awareness Day on November 16.

Professor Robert Wynn, MB BChir, MD, MRCP, FRCPath

Professor Robert Wynn, MB BChir, MD, MRCP, FRCPath

November 16 is World Sanfilippo Awareness Day, and CGTLive is taking a look at the current investigational pipeline seeking to develop a disease-modifying therapy for Sanfilippo syndrome.

Sanfilippo, also known as mucopolysaccharidosis type III (MPS III), is a lysosomal storage disorder that has 4 subtypes: MPSIIIA, MPSIIIB, MPSIIIC, and MPSIIID, with each subtype corresponding to a gene mutation that precludes the metabolism of mucopolysaccharides and leads to a deleterious buildup of heparin sulfate (HS). There is no current cure for MPSIII, and most children with the disease die in their teenage years after developmental delays.1

At this time, there are 2 main clinical, potentially disease modifying therapy programs in development for MPSIIIA, UX111 and OTL-201, from Ultragenyx and Orchard Therapeutics, respectively. UX111 is an intravenously administered self-complementary adeno-associated virus vector (AAV9)-based gene therapy vector encoding hSGSH and OTL-201 is a modified hematopoietic stem cell therapy transduced with a lentiviral vector delivering the SGSH gene. Both programs most recently reported data during February’s WORLDSymposium 2023 meeting.

Ultragenyx reported data from Cohort 3 of the phase 1/2/3 Transpher A clinical trial (NCT02716246) from 10 of 22 patients treated with a dose of 3 x 1013 vg/kg in the period prior to advanced neurodegeneration occurring.2 These 10 individuals were either younger than 2 years of age, or had baseline Development Quotient (DQ) scores of 60 or higher calculated by the Bayley Scales of Infant and Toddler Development–Third Edition, and ultimately, they reported a rapid reduction of CSF HS levels. There were no deaths, drug-related serious adverse events, or severe adverse events (AEs) reported to date in the Transpher A trial.

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Orchard reported data from its phase 1/2 trial (NCT04201405) which demonstrated an improvement in neurocognitive assessments compared with natural progression of the disease in one of the children at 18-months post-treatment.3 Three additional patients are currently within the normal cognitive development range at 9 to 18 months post-treatment but require longer follow-up to assess outcomes. Overall, treated children had higher amounts of the SGSH enzyme were seen than would be normally found in the blood and cerebrospinal fluid of healthy children. After a median of 2 years, OTL-201 achieved sustained engraftment in the bone marrow and was generally well tolerated in all the patients, although 6 serious AEs have been reported and were considered to be caused by the treatment procedure or background disease but not the OTL-201 therapy itself.

“These are encouraging results for children living with MPS-IIIA and their families, who currently have no effective treatment options,” Professor Robert Wynn, MB BChir, MD, MRCP, FRCPath, Chief Investigator on the trial at The Royal Manchester Children’s Hospital, part of Manchester University NHS Foundation Trust, said in a statement.3 “In addition to sustained engraftment of gene-corrected cells and supraphysiological SGSH enzyme levels in the periphery, the early neurocognitive findings show most patients are gaining skills in line with the development of healthy children. In 1 patient, we also have seen a marked improvement from disease natural history, and we hope to see similar results in the other patients with longer follow-up.”

A third gene therapy that recently fell out of the running is Lysogene’s LYS-SAF302, the phase 2/3 AAVance clinical trial (NCT03612869) of which failed its primary endpoint earlier this year.4 The therapy showed some efficacy for patients enrolled under the age of 30 months, but failed to meet its primary and key secondary efficacy end points for older patients, including changes in cognitive DQ, cognitive developmental age (DA), language DA, and motor DA compared to natural history. Although investigators and company executives expressed hope for the therapy in the subset of younger patients that did show some effect, the future of LYS-SAF302 seems to be shuttered as Lysogene entered liquidation proceedings in May 2023 after failing to find partners for its investigational gene therapies.5

Another stalled gene therapy is Esteve Pharmaceuticals’ EGT-101, which the company has deprioritized. Its phase 1/2 trial was fully enrolled as of April 2021 and Esteve’s 2022 annual report stated that the company was searching for a partner for the future development EGT-101 along with the gene therapy platform for the treatment of other MPS types.6

Another avenue for treating MPSIII is enzyme replacement therapy. Investigating this treatment mode is Biomarin, which reported positive data from its phase 1/2 trial (NCT02754076) of tralesinidase alfa in late 2022 and JCR Pharmaceuticals, which recently dosed its first patient in a phase 1/2 trial (NCT06095388) of JR-441, a blood-brain barrier penetrating form of heparan N-sulfatase.7,8

1. What is Sanfilippo syndrome? Cure Sanfilippo Foundation. June 23, 2023.
2. Flanagan KM, Smith N, Couce ML, et al. Interim results of Transpher A, a multicenter, single-dose clinical trial of UX111 gene therapy for Sanfilippo syndrome type A (mucopolysaccharidosis IIIA). Presented at: WORLDSymposium; February 21-26, 2023; Orlando, Florida. Abstract 118.
3. Early results of gene therapy trial for ‘childhood dementia’ show promise. News release. University of Manchester. February 24, 2023.
4. Lysogeneprovides updates and topline results from phase 2/3 AAVance gene therapy clinical study. News release. Lysogene. November 18, 2022.
5. Lysogene announces the conversion of the reorganization proceedings into judicial liquidation and its delisting. News release. Lysogene. May 26, 2023.
6. Esteve Annual Report 2022. Esteve.
7.Muschol N, Koehn A, von Cossel K, et al. A phase I/II study on intracerebroventricular tralesinidasealfa in patients with Sanfilippo syndrome type B. J Clin Invest. 2023;133(2):e165076. doi: 10.1172/JCI165076
8.JCR Pharmaceuticals announces first patient dosed in a global phase i/ii clinical trial of JR-441 for the treatment of MPS IIIA. News release. JCR Pharmaceuticals. October 27, 2023.
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