Date: 2016-03-02
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 12th Annual WORLDSymposiumTM in San Diego
Company: Synageva BioPharma (USA - MA), now Alexion Pharmaceuticals (USA - CT)
Product: SBC-103 (rhNAGLU enzyme)
Action
mechanism: enzyme replacement therapy. SBC-103 is a recombinant form of the human alpha-N-acetylglucosaminidase (NAGLU enzyme) being developed by Synageva as an enzyme replacement therapy for mucopolysaccharidosis IIIB. SBC-103 was granted orphan designation by the FDA in April 2013 and the European Medicines Agency (EMA) in June 2013 and received Fast Track designation by the FDA in January 2015. Alexion has acquired Synageva Pharma in May 2015.
Disease: mucopolysaccharidosis IIIB (Sanfilippo B syndrome)
Therapeutic area: Rare diseases - Genetic diseases
Country: UK, USA
Trial
details: This study will evaluate the safety, pharmacokinetics, and pharmacodynamics/efficacy of IV administration of recombinant human alpha-N-acetylglucosaminidase (rhNAGLU), referred to as SBC-103 for the treatment of mucopolysaccharidosis IIIB (MPS IIIB, or Sanfilippo B Syndrome). Patients are being treated in one of three different dosing cohorts (0.3 mg/kg, 1.0 mg/kg or 3.0 mg/kg) with every other week intravenous administrations of SBC-103 for 24 weeks. Patients who meet qualifying criteria may continue dosing with SBC-103 for an extended period. The primary endpoint of the trial is safety and tolerability of intravenous administration of SBC-103 in patients with MPS IIIB. The study will also evaluate the effects of dosing with SBC-103 on the change from baseline levels of total heparan sulfate (HS) in urine, serum, and cerebral spinal fluid (CSF), as well as measure the effects on neurocognitive and developmental function and change in brain structures as assessed by magnetic resonance imaging. (NCT02324049)
Latest
news: * On March 2, 2016, Alexion Pharmaceuticals announced that researchers presented 24-week results from an ongoing open-label, Phase I/II trial of intravenous SBC-103 (rhNAGLU enzyme) in children with mucopolysaccharidosis IIIB . Data from this study showed a 26.2 percent mean reduction from baseline in total heparan sulfate (HS) levels in cerebrospinal fluid (CSF) at 24 weeks in the highest dose studied (3 mg/kg every other week [qow]). These data were presented in a late-breaking poster at the 12th Annual WORLDSymposiumTM in San Diego . Eleven children with MPS IIIB (ages 2 years to 10 years at study entry) were enrolled in the first-in-human study, which included three parallel dosing groups of intravenous SBC-103 (0.3, 1.0 and 3.0 mg/kg qow). The primary endpoint of the ongoing trial is safety and tolerability, and key secondary endpoints presented at WORLDSymposium include changes from baseline in HS levels in CSF and serum as well as pharmacokinetics (PK) and pharmacodynamics (PD). Additional secondary endpoints related to neurocognitive outcomes, brain structure, and changes in HS levels in urine are also being evaluated. * On July 14, 2016, Alexion Pharmaceuticals announced that researchers presented new data from an ongoing open-label, Phase 1/2 trial of intravenous SBC-103 (rhNAGLU enzyme) in children with mucopolysaccharidosis IIIB. Preliminary evidence, based on brain scans and neurocognitive assessments at 24 weeks, showed the potential for disease stabilization in patients with MPS IIIB treated with SBC-103.1 These data were presented at the 14th International Symposium on MPS and Related Diseases in Bonn, Germany. Researchers presented preliminary results for volumetric brain MRI and neurocognitive assessments performed after 24 weeks of IV SBC-103 at 0.3, 1, or 3 mg/kg every other week (QOW). MRI scans for those dosed at 3 mg/kg showed that 3 out of 4 patients had an increase or no change (-1% to +1%) in CGM volume compared to baseline suggesting a potential for disease stabilization at this dose. In the 1 mg/kg group and 0.3 mg/kg group, MRI scans showed that 2 out of 3 and 0 out of 3 patients respectively had an increase or no change in CGM volume compared to baseline. In the neurocognitive assessments for the 3 mg/kg group, 3 out of 4 patients had an increase in both mental age equivalent (AEq) and developmental quotient (DQ) compared to baseline. For the 1 mg/kg group, 2 out of 4 patients had an increase in both AEq and DQ compared to baseline, and for 0.3 mg/kg group, 1 out of 3 patients had an increase in both AEq and DQ compared to baseline. Overall, response profiles among the 3 mg/kg treatment groups suggest a potential dose effect as compared to the 0.3 mg/kg and 1 mg/kg groups. Eleven children with MPS IIIB (ages 2 years to 10 years at study entry) were enrolled in this first-in-human study, which included three parallel dosing groups of intravenous SBC-103 (0.3, 1.0 and 3.0 mg/kg QOW). The primary endpoint of the ongoing trial is safety and tolerability, and key secondary endpoints presented at MPS 2016 include effect of SBC-103 on total HS levels in cerebrospinal fluid (CSF) and serum, brain structures (MRI) and neurocognitive status, and pharmacokinetic (PK) profile of SBC-103. During 24 weeks of treatment with SBC-103 at the highest dose of 3 mg/kg, most adverse events (AEs) were mild in severity and no patient discontinued the study. Two patients experienced a total of four serious AEs (bacteremia, pyrexia, staphylococcal bacteremia, and cyanosis [pre-treatment]) that were deemed not related to SBC-103. Seven infusion-associated reactions occurred in three patients (pyrexia, chills, hypertension, and tachycardia).1 As previously presented at the 12th Annual WORLDSymposiumTM, patients treated with SBC-103 had a 26.2 percent mean reduction from baseline in total HS levels in CSF at 24 weeks in the highest dose studied (3 mg/kg QOW). Additionally, at week 24, patients in the 0.3 mg/kg and 1.0 mg/kg groups had a 10.9 percent mean increase and a 0.4 percent mean decrease in HS CSF, respectively. HS reduction in CSF was linearly correlated with SBC-103 serum PK exposures. Total change from baseline in serum HS was -39.6 percent, -53.9 percent and -40.5 percent for 0.3 mg/kg, 1 mg/kg, and 3 mg/kg groups, respectively.8 * On June 4, 2015, Synageva BioPharma, a biopharmaceutical company developing therapeutic products for rare disorders, announced the completion of enrollment in a Phase 1/2 trial with SBC-103 in patients with mucopolysaccharidosis IIIB. The trial reached its targeted enrollment of nine patients, who are two years of age or greater but less than 12 years of age, with a definitive diagnosis of MPS IIIB and developmental delay. * On January 26, 2015, Synageva BioPharma has begun as part of a Phase 1/2 study. The trial will enroll approximately nine patients, two years of age or greater but less than 12 years of age, with definitive diagnosis of MPS IIIB and developmental delay. Patients will be treated in one of three different dosing cohorts (0.3 mg/kg, 1.0 mg/kg or 3.0 mg/kg) with every other week intravenous administrations of SBC-103 for 24 weeks. Patients who meet qualifying criteria may continue therapy with SBC-103 for an extended treatment period that will last up to 128 weeks. The primary endpoint of the trial is safety and tolerability of intravenous administration of SBC-103 in patients with MPS IIIB. The study will also determine the effects of dosing with SBC-103 on the onset, magnitude, and reversibility of changes in levels of total HS in cerebral spinal fluid (CSF), serum, and urine as well as measure the effects of neurocognitive and developmental function and change in brain structures as assessed by magnetic resonance imaging. Exploratory biomarkers, SBC-103 concentration in CSF, MPS IIIB disease characteristics, symptoms, and quality of life will also be measured. The company plans to report preliminary data from this study during the second half of this year.
Most adverse events (AEs) in the study were mild and unrelated to SBC-103, and no patient discontinued the study. Of 11 patients in the study, two patients experienced a total of four serious AEs (bacteremia, pyrexia, staphylococcal bacteremia, and cyanosis [pre-treatment]) that were deemed not related to SBC-103. Six infusion-associated reactions occurred in three patients (pyrexia, chills, hypertension, and tachycardia).
At 24 weeks of treatment, the analysis showed a 26.2 percent mean reduction from baseline in total HS CSF in the 3 mg/kg (N=4) dosing cohort. These data are directionally consistent with reductions in brain HS observed in the NAGLU -/- mouse model. Patients in the 0.3 mg/kg (N=3) and 1.0 mg/kg (N=4) groups had a 10.9 percent mean increase and a 0.4 percent mean decrease in HS CSF, respectively. Additionally, researchers reported mean reductions in total serum HS at 24 weeks of 39.6 percent, 53.9 percent, and 40.5 percent at 0.3, 1.0 and 3.0 mg/kg, respectively. These findings are directionally consistent with reductions in liver HS observed in the NAGLU -/- mouse model. Researchers also reported PK findings for SBC-103 at 24 weeks, noting that individual HS CSF reduction levels were linearly correlated with an increase in serum PK exposures.1
An interim 12-week analysis from the Phase 1/2 study reported in December 2015 showed a dose-dependent reduction of HS levels in CSF in the three dosing cohorts (mean reductions of 3 percent, 6 percent and 11 percent at 0.3 mg/kg [N=3], 1.0 mg/kg [N=4], and 3.0 mg/kg [N=3], respectively). One patient who received only one 3 mg/kg and one 1 mg/kg dose (instead of 6 doses at 3 mg/kg) due to an unrelated SAE was excluded from this analysis, and restarted treatment at week 8.
