Delving into the Latest Updates on Modified recombinant human sulphamidase(Swedish Orphan Biovitrum) with Synapse

Overview

Basic Info

Drug Type

Enzyme

Synonyms

Recombinant-sulfamidase-Swedish-Orphan-Biovitrum

Target-

Mechanism-

Therapeutic Areas

Congenital DisordersEndocrinology and Metabolic DiseaseSkin and Musculoskeletal Diseases+ [1]

Active Indication

Mucopolysaccharidosis III

Inactive Indication-

Originator Organization

Swedish Orphan Biovitrum AB

Active Organization

UCSF Benioff Children's Hospital Oakland

Swedish Orphan Biovitrum AB

Inactive Organization-

Drug Highest PhasePhase 1/2

First Approval Date-

RegulationFast Track (US)

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MPS IIIA, also known as Sanfilippo A, is an inherited lysosomal storage disease (LSD). MPS IIIA is caused by a deficiency in sulfamidase, one of the enzymes involved in the lysosomal degradation of the glycosaminoglycan (GAG) heparan sulfate (HS). The natural course of MPS IIIA is characterized by devastating neurodegeneration with initially mild somatic involvement. The aim of the present study is to assess the safety, tolerability and efficacy of long-term SOBI003 treatment. SOBI003 is a chemically modified recombinant human (rh) Sulfamidase developed as an enzyme replacement therapy (ERT).

Start Date19 Jan 2019

Sponsor / Collaborator

Swedish Orphan Biovitrum AB

NCT03423186 / CompletedPhase 1/2

An Open, Non-controlled, Parallel, Ascending Multiple-dose, Multicenter Study to Assess Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of SOBI003 in Pediatric MPS IIIA Patients

MPS IIIA, also known as Sanfilippo A, is an inherited lysosomal storage disease (LSD). MPS IIIA is caused by a deficiency in sulfamidase, one of the enzymes involved in the lysosomal degradation of the glycosaminoglycan (GAG) heparan sulfate (HS). The natural course of MPS IIIA is characterized by devastating neurodegeneration with initially mild somatic involvement. The aims of the present study is to assess the dose related safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SOBI003, a chemically modified recombinant human (rh) Sulfamidase developed as an enzyme replacement therapy (ERT).

Start Date19 Jun 2018

Sponsor / Collaborator

Swedish Orphan Biovitrum AB

100 Clinical Results associated with Modified recombinant human sulphamidase(Swedish Orphan Biovitrum)

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100 Translational Medicine associated with Modified recombinant human sulphamidase(Swedish Orphan Biovitrum)

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100 Patents (Medical) associated with Modified recombinant human sulphamidase(Swedish Orphan Biovitrum)

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5

Literatures (Medical) associated with Modified recombinant human sulphamidase(Swedish Orphan Biovitrum)

01 Aug 2022·Molecular Genetics and Metabolism

Chemically modified recombinant human sulfamidase (SOBI003) in mucopolysaccharidosis IIIA patients: Results from an open, non-controlled, multicenter study

Article

Author: Huledal, Gunilla ; Bröijersén, Anders ; Harmatz, Paul ; Dalén, Per ; Wikén, Margareta ; Ezgü, Fatih ; Gelius, Stefan Svensson ; Önnestam, Kristin ; Lindqvist, Daniel ; Muenzer, Joseph

PURPOSEMucopolysaccharidosis IIIA (MPS IIIA) is an inherited lysosomal storage disorder caused by mutations in the N-sulfoglucosamine sulfohydrolase gene that result in deficient enzymatic degradation of heparan sulfate (HS), resulting in progressive neurodegeneration in early childhood and premature death. A chemically modified variant of recombinant human sulfamidase, SOBI003, has shown to cross the blood-brain barrier (BBB) in mice and achieve pharmacologically relevant levels in cerebrospinal fluid (CSF). We report on a phase 1/2, open-label, first-in-human (FIH) study (NCT03423186) and its extension study (NCT03811028) to evaluate the long-term safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and clinical efficacy of SOBI003 in patients with MPS IIIA for up to 104 weeks.METHODSSix patients aged 1-6 years with confirmed MPS IIIA with developmental age ≥ 12 months received weekly intravenous injections of SOBI003 at 3 mg/kg (Cohort 1, n = 3) or 10 mg/kg (Cohort 2, n = 3). During the extension study, the individual dose of SOBI003 could be adjusted up to 20 mg/kg at the discretion of the investigator.RESULTSSOBI003 was generally well tolerated. Serum concentrations of SOBI003 increased in proportion to dose, and presence in CSF confirmed that SOBI003 crosses the BBB. Anti-drug antibodies (ADA) were detected in serum and CSF in all patients, with subsequent reductions in serum SOBI003 exposure at high ADA titers. SOBI003 exerted a clear PD effect: a mean reduction in HS levels in CSF of 79% was recorded at the last assessment, together with reductions in HS levels in serum and urine. Neurocognitive development age-equivalent scores showed a stabilization of cognition for all patients, whereas no clear overall clinical effect was observed on adaptive behavior, sleep pattern or quality of life.CONCLUSIONSOBI003 was well tolerated when administered as weekly intravenous infusions at doses of up to 20 mg/kg for up to 104 weeks. ADA development was common and likely affected both PK and PD parameters. SOBI003 crossed the BBB and showed pharmacological activity on HS in CSF.

01 May 2017·Journal of Inherited Metabolic DiseaseQ2 · MEDICINE

Slow, continuous enzyme replacement via spinal CSF in dogs with the paediatric‐onset neurodegenerative disease, MPS IIIA

Q2 · MEDICINE

Article

Author: Hopwood, John J ; Marshall, Neil R ; Hassiotis, Sofia ; Jolly, Robert D ; King, Barbara ; Tucker, Justin ; Hattersley, Kathryn ; Trim, Paul J ; Hemsley, Kim M ; Snel, Marten F

AbstractIntra‐cerebrospinal fluid (CSF) injection of recombinant human lysosomal enzyme is a potential treatment strategy for several neurodegenerative lysosomal storage disorders including Sanfilippo syndrome (Mucopolysaccharidosis type IIIA; MPS IIIA). Here we have utilised the MPS IIIA Huntaway dog model to compare the effectiveness of the repeated intermittent bolus injection strategy being used in the trials with an alternate approach; slow, continual infusion of replacement enzyme (recombinant human sulphamidase; rhSGSH) into the spinal CSF using a SynchroMed II® pump attached to a spinal infusion cannula. The ability of each enzyme delivery strategy to ameliorate lesions in MPS IIIA brain was determined in animals treated from ∼three‐ to six‐months of age. Controls received buffer or no treatment. Significant reductions in heparan sulphate (primary substrate) were observed in brain samples from dogs treated via either cisternal or lumbar spinal CSF bolus injection methods and also in slow intra‐spinal CSF infusion‐treated dogs. The extent of the reduction differed regionally. Pump‐delivered rhSGSH was less effective in reducing secondary substrate (GM3 ganglioside) in deeper aspects of cerebral cortex, and although near‐amelioration of microglial activation was seen in superficial (but not deep) layers of cerebral cortex in both bolus enzyme‐treated groups, pump‐infusion of rhSGSH had little impact on microgliosis. While continual low‐dose infusion of rhSGSH into MPS IIIA dog CSF reduces disease‐based lesions in brain, it was not as efficacious as repeated cisternal or spinal CSF bolus infusion of rhSGSH over the time‐frame of these experiments.

01 May 2016·Journal of NeurochemistryQ2 · MEDICINE

Low‐dose, continuous enzyme replacement therapy ameliorates brain pathology in the neurodegenerative lysosomal disorder mucopolysaccharidosis type IIIA

Q2 · MEDICINE

Article

Author: Snel, Marten F. ; Hassiotis, Sofia ; Beard, Helen ; Hopwood, John J. ; King, Barbara ; Trim, Paul J. ; Hemsley, Kim M. ; Rozaklis, Tina

AbstractRepeated replacement of sulphamidase via cerebrospinal fluid injection is an effective treatment for pathological changes in the brain in mice and dogs with the lysosomal storage disorder, mucopolysaccharidosis type IIIA (MPS IIIA). Investigational trials of this approach are underway in children with this condition, however, infusions require attendance at a specialist medical facility. We sought to comprehensively evaluate the effectiveness of sustained‐release (osmotic pump‐delivered) enzyme replacement therapy in murine MPS IIIA as this method, if applied to humans, would require only subcutaneous administration of enzyme once the pump was installed. Six‐week‐old MPS IIIA and unaffected mice were implanted with subcutaneous mini‐osmotic pumps connected to an infusion cannula directed at the right lateral ventricle. Either recombinant human sulphamidase or vehicle were infused over the course of 7 weeks, with pumps replaced part‐way through the experimental period. We observed near‐normalisation of primarily stored substrate (heparan sulphate) in both hemispheres of the MPS IIIA brain and cervical spinal cord, as determined using tandem mass spectrometry. Immunohistochemistry indicated a reduction in secondarily stored GM3 ganglioside and neuroinflammatory markers. A bias towards the infusion side was seen in some, but not all outcomes. The recombinant enzyme appears stable under pump‐like conditions for at least 1 month. Given that infusion pumps are in clinical use in other nervous system disorders, e.g. for treatment of spasticity or brain tumours, this treatment method warrants consideration for testing in large animal models of MPS IIIA and other lysosomal storage disorders that affect the brain.

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Clinical trials of repeated injection of replacement enzyme into CSF are underway in patients with the inherited neurodegenerative disorder mucopolysaccharidosis type IIIA. In this pre‐clinical study, we examined an alternative approach – slow, continual infusion of enzyme using pumps. We observed significant reductions in substrate accumulation and other disease‐based lesions in treated mouse brain. Thus, the strategy warrants consideration for testing in large animal models of MPS IIIA and also in other neurodegenerative lysosomal storage disorders.

100 Deals associated with Modified recombinant human sulphamidase(Swedish Orphan Biovitrum)

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External Link

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Mucopolysaccharidosis III	Phase 1	DE	Swedish Orphan Biovitrum AB	19 Jun 2018
Mucopolysaccharidosis III	Phase 1	TR	Swedish Orphan Biovitrum AB	19 Jun 2018
Mucopolysaccharidosis III	Phase 1	US	Swedish Orphan Biovitrum AB	19 Jun 2018

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03423186 \| NCT03811028 (SOBI003, Pubmed) Manual	Phase 1/2	Mucopolysaccharidosis III	6	SOBI003	pxqpttafci(sjbwegbcup) = sppoypdcyb gtmpqlrdxt (bjhkvzwdwq )	Positive	28 Jun 2022
NCT03811028 (CTgov)	Phase 1/2	Mucopolysaccharidosis III	6	SOBI003 (Dose Group 1)	(ylqdqbrekl) = rlszqkjwij vbhpvpmsfm (yfbyumgjpm, qyhyiksdtv - uvssezrrvs) View more	-	25 Feb 2022
				SOBI003 (Dose Group 2)	(ylqdqbrekl) = reqylykrmp vbhpvpmsfm (yfbyumgjpm, wkhehydcvc - cuzytmdmbd) View more
NCT03423186 (CTgov)	Phase 1/2	Mucopolysaccharidosis III	6	SOBI003 (Dose Group 1)	(tnefqbuqly) = tuuacxjmej mikdvysfqq (mdiqwumrqq, mbpxzxmbvu - apxlvmmoyo) View more	-	22 Apr 2021
				SOBI003 (Dose Group 2)	(tnefqbuqly) = obelgkibrj mikdvysfqq (mdiqwumrqq, dhzerdethr - fakjeeamvs) View more