Orchard Therapeutics’ OTL-201, an investigational genetically-modified hematopoietic stem cell (HSC) therapy intended to treat mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome), has demonstrated the ability to reduce levels of the disease-associated substrate heparan sulphate (HS) in the plasma, urine, and cerebrospinal fluid (CSF) of patients treated in a phase 1/2 clinical trial (NCT04201405). The data were presented in a poster by Simon Jones, MBChB BSc MRCPCH, a consultant in pediatric inherited metabolic disease at St Mary’s Hospital, at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.
Among the 5 patients treated in the study, sustained supraphysiological expression of the disease-targeted gene, SGSH, was rapidly achieved in the leukocytes and the plasma. By 6 to 12 months posttreatment, SGSH expression in the CSF reached or exceeded the normal range; these levels were maintained to the most recent follow-up. Furthermore, all patients showed a sustained reduction of more than 82% from baseline in plasma HS and more than 90% from baseline in urine HS, reaching the normal range for urine HS. A reduction in CSF HS was also observed and maintained, as was a reduction in total GAG per creatine ratio. It was noted that rapid engraftment and multilineage expression was evinced via vector copy number analysis. Four of the 5 treated patients’ results on the Bayley Scale of Infant and Toddler Development indicated gain of skills in line with normal childhood development. Observations of continence and complex play not typically seen in children with severe MPSIIIA were reported in these participants. Four of the 5 patients progressed from the Bayley scale to the Kaufman Assessment Battery for Children at ages ranging from 37 months to 47.5 months.
- Among the 5 patients treated in the study, sustained supraphysiological expression of the disease-targeted gene, SGSH, was rapidly achieved in the leukocytes and the plasma.
- All patients showed a sustained reduction of more than 82% from baseline in plasma HS and more than 90% from baseline in urine HS, reaching the normal range for urine HS. A reduction in CSF HS was also observed and maintained.
- In terms of safety, 6 serious adverse events (SAEs) were reported among 3 of the 5 treated patients, but none weredeemeddirectly related to OTL-201.
In terms of safety, 6 serious adverse events (SAEs) were reported among 3 of the 5 treated patients, but none were deemed directly related to OTL-201. These SAEs included a grade 2 case of fever that occurred before the myeoloablative conditioning regimen, a grade 1 case of fever that occurred before OTL-201 administration, a case of sinusoidal obstructive disease, a case of subdural haematoma, a case of delayed engraftment, and a sedation complication. Regarding the delayed engraftment SAE, Jones and colleagues noted that clear engraftment of neutrophils and reticulocytes occurred at day 28 and day 41 postinfusion, respectively, but platelet engraftment was not achieved until day 52. Delayed engraftment was defined as engraftment occurring 42 days or more after infusion. The case was considered likely to have been caused by primary cytomegalovirus viraemia that occurred around the time of the infusion. There was no evidence of insertional mutagenesis or replication competent lentiviral particles observed in the study. AntiSGSH antibodies were observed and rapidly increased by day 30 postinfusion to 3 months postinfusion, but reduced over time. The titers were deemed unlikely to be clinically significant, with there being no indication that the antiSGSH antibody levels affected HS levels or the activity of the SGSH enzyme.
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The 5 patients in the study were aged 6.2 months, 8.6 months, 18.3 months, 23.3 months, and 23.6 months at the time of treatment. All patients had rapidly progressive MPSIIIA and received full intensity busulfan conditioning and 2 days of rest before administration of the investigational therapy. OTL-201 consists of autologous HSCs that have been genetically modified with a lentiviral vector outside the body to express SGSH with a CD11b promoter.
“Treatment was generally well-tolerated, and led to robust, prompt, sustained, multilineage engraftment of genetically modified cells," Jones and colleagues concluded. “[There was] physiological and supraphysiological levels of SGHS enzyme in leukocytes, plasma, and CSF with rapid and significant reduction of substrate observed in all compartments... Neurocognitive trial data [is] early, but 4 of 5 patients progressed onto the Kaufman instrument, suggestive of modification of neurological phenotype.”
1. Jones S, Kinsella J, Holley RJ, et al. Clinical outcomes and sustained biochemical engraftment following ex-vivo autologous stem cell gene therapy for mucopolysaccharidosis type IIIA. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #166