New Medicines

Mucopolysaccharidosis IIIA (MPS IIIA - Sanfilippo syndrome)


New molecular entity
Sarepta Therapeutics

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Nov 21Registrational trial is fully recruited with top-line data expected in H2 22. Lysogene has reported positive LYS-SAF302 biomarkers demonstrating biological activity [5].
Jan 21Also has rare paediatric disease designation in the US [3].
Feb 20FDA grants fast track designation to LYS SAF302 for the treatment of MPS IIIA [3].
Oct 18Sarepta Therapeutics and Lysogene enter into a licensing agreement for LYS SAF302. Lysogene shall be responsible for completion of the pivotal trial. Sarepta shall have exclusive commercial rights to LYS SAF302 in the US and all territories outside of Europe, and Lysogene will retain exclusive commercial rights to LYS SAF302 in Europe [3].
Dec 17Granted orphan drug status in EU [3].
Nov 15Granted orphan drug status in US [3].


An adeno-associated viral vector serotype 10 (rAAVrh.10) carrying the human N-sulfoglucosamine sulfohydrolase (hSGSH). The missing gene SGSH is delivered directly to the CNS in a neurosurgical procedure to provide a permanent source of the missing enzyme.
Mucopolysaccharidosis III is considered the most common of the mucopolysaccharidosis genetic disorders, occurring with an incidence of 1 in 70,000 newborns. Sanfilippo syndrome results from the deficiency or absence of 4 different enzymes that are necessary to degrade the GAG heparan sulfate. Each enzyme deficiency defines a different subtype of Sanfilippo syndrome, as follows: type IIIA (Sanfilippo A), type IIIB (Sanfilippo B), type IIIC (Sanfilippo C), and type IIID (Sanfilippo D) [1].
Mucopolysaccharidosis IIIA (MPS IIIA - Sanfilippo syndrome)

Trial or other data

Jul 22Lysogene announces additional preliminary data from AAVance. A positive effect of LYS-SAF302 on the MPS IIIA disease biomarker heparan sulfate (HS) in the cerebrospinal fluid (CSF) was confirmed in additional subjects and at additional timepoints relative to previously communicated partial data. Statistically significant decreases of about 20% in average levels of total HS-derived oligosaccharides in the CSF relative to baseline levels were observed at 6, 12 and 24 months after dosing with LYS-SAF302. HS levels at 24 months after dosing with LYS-SAF302 (1654 ± 497 ng/ml, mean ± SD, n=15) were decreased by 22% relative to baseline levels (2159 ± 589 ng/ml, mean ± SD, n=16), p=0.015 by Student´s t test (preliminary analysis). No statistically significant effect on serum HS levels was observed at 6, 12 or 24 months after dosing with LYS-SAF302. These results confirm the biological activity of LYS-SAF302 gene therapy treatment. They are consistent with the intraparenchymal mode of administration of LYS-SAF302, which is expected to lead to a specific decrease of HS in the brain, but not in the systemic circulation nor in other tissues, including the spinal cord. The previous observation that treatment with LYS-SAF302 led to a transient increase in serum neurofilament light (NFL) levels, likely due to transient axonal damage caused by brain surgery, followed by a decrease below baseline levels, was confirmed in additional subjects and at additional timepoints. Moreover, a similar effect was demonstrated in the CSF. In the serum, NFL levels decreased by 33% (n=12, p=0.026) and 41% (n=16, p=0.0075) below baseline levels (113 ± 50 pg/ml, mean ± SD, n=19), 18 and 24 months after dosing with LYS-SAF302, respectively. In the CSF, NFL levels decreased by 33% (n=15, p=0.025) below baseline levels (3.7 ± 1.5 ng/ml, mean ± SD, n=17) 24 months after dosing with LYS-SAF302. All statistical analyses were done by Student’s t test and are preliminary. These results suggest that treatment with LYS-SAF302 led to a decrease in neuronal damage relative to baseline at 18 and 24 months after drug administration. Three subjects in AAVance, treated at 10, 13 and 31 months of age, present continuous increase of cognitive, language and motor functions 24 months after dosing with LYS-SAF302, as assessed by the BSID-III (Bayley’s Scales of Infant Development, Third edition). Two of these subjects have a cognitive developmental age (DA) at 24 months after dosing with LYS-SAF302 that is 5-6 months higher (41 and 42, respectively) than the highest cognitive DA (35) observed in natural history studies of MPS IIIA (Shapiro et al, 2016; Wijburg et al 2022). Remarkably, one of these subjects is homozygous for a severe mutation (deletion) and the other subject is compound heterozygous for two severe mutations (a duplication and a deletion). The third subject with continuously increasing DA at 24 months after dosing with LYS-SAF302 is a compound heterozygote for a severe mutation and a S298P mutation, which may give rise to either a classical severe or an intermediate phenotype. Longer follow-up is warranted to confirm positive evolution of development in this patient. Three other subjects, treated at 24, 30 and 31 months of age, have stable cognitive DA relative to baseline, as assessed by the BSID-III scale, and stable or continuously increasing BSID-III language and motor development scores at 24 months after dosing with LYS-SAF302. Two of these subjects have SGSH missense mutations associated with the classical severe phenotype of MPS IIIA. One subject has a severe mutation on one allele and a mutation with unknown effect on disease severity on the second allele. The fact that developmental progression or stabilization is seen in subjects with mutations associated with the classical severe disease phenotype suggests that early therapeutic intervention with LYS-SAF302 can protect children with MPS IIIA from decline of cognitive, language, and motor functions. The AAVance trial Month 24 database lock took place as planned on 1st of July 2022. Full study results are expected by mid-Sep 2022, along with results from the PROVide patient reported outcome videos study [8].
May 22Preliminary results from AAVance announced. In patients who have been followed for at least 2 years, there has been improvement, stabilisation, or slowing down of decline in cognitive developmental age (DA) in about half. Notably, in all 6 patients enrolled under the age of 30 months, a persistent increase or stabilisation of the cognitive, language and motor domains of the BSID-III was observed in the 24 months period post-treatment. Two of these 6 patients, including 1 patient over 4 years of age, have already exceeded by several months the highest cognitive DA (35 months) observed in the natural history cohort. The 2 patients reached 41 and 42 months of cognitive DA in the 24 months period post-treatment with an increase of 25 and 17 months compared to their baseline, respectively [7].
Nov 21UK trial site for the PII/III AAVance trial was Great Ormond Street Hospital [6].
Nov 21Lysogene reports that the clinical hold has had no anticipated impact on current clinical trial timelines, as primary and secondary endpoints are based on analysis of already treated subjects (main cohort >30m fully enrolled). All subjects remain in the study and are being followed per protocol, with ongoing investigations and follow-up, MRIs showing trend to stabilization or decrease of white matter abnormalities for all subjects post-12 months visit, and no clinical sequelae directly attributable to white matter abnormalities [5].
Aug 21PII/III AAVance trial is not recruiting and collection of primary outcome data is still expected to complete Mar 22 [4].
Oct 20Lysogene reports a death of a child patient in the AAVance trial. At the time of reporting, the reason of death was unknown and there was no evidence to establish causal relationship with the treatment of olenasufligene relduparvovec [3].
Jul 20The company received a letter from the US FDA confirming the clinical hold for recruitment and treatment of new patients in the AAVance trial. The US FDA issued a clinical hold for the trial in June 2020. The clinical hold follows observations in some patients of localised findings on MRI images at the intracerebral injection sites. The company has discussed a path forward with FDA and is looking to gather additional information on the drug ´s safety profile. As of June 2020, 19 out of 20 patients treated, and all patients remain in the study and are being followed per study protocol [3].
Dec 18Pivotal PII/III AAVance trial to assess the efficacy of olenasufligene relduparvovec (LYS SAF302) in improving or stabilising the neurodevelopmental state of MPS IIIA patients starts (NCT03612869; P078-2018; P4SAF302). The open-label trial is enrolling 20 patients aged 6 months and older in the US, UK, France, Netherlands and Germany. Primary outcome is change from baseline in development quotient (DQ), compared to regression reported in natural history studies at month 6, 12, 18, 24. Development Quotient will be measured for each patient using one of two standard instruments, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) or the Kaufman Assessment Battery for Children, Second Edition (KABC-II), based on age and ability range. The development quotient (DQ) is a means to express a neurodevelopmental/cognitive delay which is computed as a ratio and expressed as a percentage using the development age (DA) score divided by the age at testing ([development age score/chronological age] × 100; range: 0 - 100, where high values are desirable). Collection of primary outcome data is due to complete Mar 22 [2].
Mar 17Lysiogene announces completion of the recruitment of 23 patients with MPS IIIA in an observational SAMOS study. The prospective natural history study intended to recruit patients who will not receive olenasufligene relduparvovec (LYS SAF302) but will receive study-related care. The results secured from the study will enable optimal trial design, greater understanding of disease progression and better predictions of future therapeutic effects of olenasufligene relduparvovec [3].